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Pattern recognition receptor

Pattern recognition receptors (PRRs) are a class of germline-encoded proteins expressed by cells involved in innate immunity across animals and plants, including immune cells like macrophages, dendritic cells, and neutrophils, as well as non-immune cells, that detect conserved molecular motifs known as pathogen-associated molecular patterns (PAMPs) from microbes and damage-associated molecular patterns (DAMPs) from stressed or damaged host cells.^[1] These receptors enable the innate immune system to rapidly distinguish between self and non-self entities, triggering immediate defensive responses without prior antigen exposure.^[2] By recognizing broad structural features rather than specific antigens, PRRs form the foundational layer of immunity, bridging innate and adaptive responses through cytokine production and antigen presentation.^[1] The concept of PRRs originated from the work of immunologist Charles A. Janeway Jr., who in 1989 proposed that innate immunity relies on receptors evolved to recognize invariant patterns in pathogens, challenging the prevailing focus on adaptive immunity.^[3] This hypothesis gained empirical support in the mid-1990s when Jules A. Hoffmann identified the Toll receptor in Drosophila melanogaster as essential for antifungal defense, revealing a conserved innate sensing mechanism.^[3] Shortly thereafter, in 1998, Bruce A. Beutler discovered that the mammalian Toll-like receptor 4 (TLR4) mediates responses to bacterial lipopolysaccharide (LPS), linking PRRs to sepsis and inflammation; these breakthroughs earned Hoffmann, Beutler, and Ralph M. Steinman the 2011 Nobel Prize in Physiology or Medicine.^[3] PRRs are categorized into several families based on their cellular localization, ligand specificity, and signaling domains, including extracellular and endosomal Toll-like receptors (TLRs), cytosolic nucleotide-binding oligomerization domain-like receptors (NLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma 2-like receptors (ALRs), with additional sensors like cyclic GMP-AMP synthase (cGAS).^[1] TLRs, the most studied group, comprise 10 functional members in humans that detect diverse PAMPs such as bacterial lipopeptides, viral double-stranded RNA, and fungal zymosan.^[1] Cytosolic PRRs like NLRs and RLRs monitor intracellular threats, forming inflammasomes or activating interferon pathways upon detecting bacterial peptidoglycans or viral RNA, respectively.^[2] Upon ligand engagement, PRRs initiate intracellular signaling cascades via adaptor proteins like MyD88, TRIF, or MAVS, culminating in the activation of transcription factors such as NF-κB and IRF3/7 to induce proinflammatory cytokines (e.g., TNF-α, IL-1β), type I interferons, and antimicrobial peptides.^[2] These responses not only contain infections but also promote adaptive immunity by enhancing antigen presentation and T-cell priming on dendritic cells.^[1] Regulatory mechanisms, including inhibitory receptors and post-translational modifications like ubiquitination, fine-tune PRR activity to prevent excessive inflammation.^[2] Beyond infection control, PRRs contribute to sterile inflammation in conditions like atherosclerosis, neurodegeneration, and cancer, where DAMPs from necrotic cells amplify tissue damage.^[2] Dysregulation of PRR pathways underlies autoimmune diseases (e.g., rheumatoid arthritis via TLRs) and chronic inflammatory disorders, while their therapeutic modulation—through agonists like TLR4 activators in vaccines or inhibitors targeting NLRP3 inflammasomes—holds promise for treating infections, autoimmunity, and tumors.^[2] Recent discoveries since 2021, including cGAS-STING interactions with gut microbiota and epigenetic regulation of "trained immunity," underscore the evolving role of PRRs in systemic homeostasis and personalized medicine.^[2]

Overview

Definition and functions

Pattern recognition receptors (PRRs) are a class of germline-encoded proteins that serve as sentinel sensors in the innate immune system, enabling host cells to detect and respond to invading pathogens and endogenous danger signals without prior exposure or sensitization. These receptors are constitutively expressed on the surface or within various cell types, including both immune cells like macrophages and dendritic cells, as well as non-immune cells such as epithelial cells, allowing for broad surveillance across tissues. By recognizing highly conserved molecular motifs, PRRs distinguish between self and non-self entities, initiating rapid protective responses that bridge innate and adaptive immunity.^[4]^[1]^[5] The primary ligands for PRRs include pathogen-associated molecular patterns (PAMPs), which are evolutionarily conserved structures unique to microorganisms, such as lipopolysaccharide (LPS) from Gram-negative bacteria, flagellin from bacterial flagella, double-stranded RNA (dsRNA) from viruses, peptidoglycan from bacterial cell walls, and β-glucans from fungal cell walls. Additionally, PRRs detect damage-associated molecular patterns (DAMPs) released during cellular stress, injury, or necrosis, exemplified by high-mobility group box 1 (HMGB1) protein and extracellular ATP. Upon ligand binding, PRRs trigger multifaceted immune functions, including the production of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) to amplify inflammation, enhancement of phagocytosis and autophagy for pathogen clearance, and activation of antigen-presenting cells to prime adaptive immune responses. These actions collectively promote host defense against infections and sterile tissue damage while maintaining immune homeostasis.^[4]^[1]^[5] PRRs exhibit diverse localization to maximize detection efficiency: membrane-bound forms operate at the extracellular surface or in endosomal compartments to sense external or internalized threats, cytoplasmic variants monitor intracellular invaders, and secreted forms circulate in bodily fluids for systemic surveillance. For instance, Toll-like receptors (TLRs) represent membrane-bound PRRs, while NOD-like receptors (NLRs) function in the cytosol. This strategic distribution underscores the evolutionary advantage of PRRs, providing a non-clonal, immediate response mechanism that is essential for survival against diverse microbial challenges and injury, predating adaptive immunity in evolutionary history.^[4]^[1]^[5]

Historical background

In 1989, Charles Janeway Jr. proposed the concept of pattern recognition receptors (PRRs), predicting that germline-encoded receptors in the innate immune system would detect conserved microbial patterns to initiate immune responses, shifting emphasis from the previously dominant adaptive immunity paradigm.^[6] This theoretical framework gained experimental validation in 1996 when Bruno Lemaitre and colleagues identified the Toll receptor in Drosophila melanogaster as a key antifungal PRR, demonstrating its role in inducing antimicrobial peptide production against fungal infections.^[7] Building on this invertebrate discovery, Ruslan Medzhitov and Charles Janeway Jr. extended the concept to mammals in 1997 by cloning human Toll-like receptor 4 (TLR4) and showing its activation of NF-κB signaling in response to microbial stimuli, with subsequent 1998 studies linking TLR4 specifically to lipopolysaccharide (LPS) recognition from Gram-negative bacteria.^[8] Subsequent milestones expanded the PRR repertoire: in 2002, Naohiro Inohara et al. described the NOD-like receptor (NLR) family as cytosolic sensors of bacterial components, regulating inflammation and host defense. In 2004, Mitsutoshi Yoneyama et al. identified RIG-I-like receptors (RLRs) as cytoplasmic detectors of viral double-stranded RNA, triggering type I interferon production. The discovery continued in 2013 with Lijun Sun et al. revealing cyclic GMP-AMP synthase (cGAS) as a cytosolic DNA sensor that generates the second messenger cGAMP to activate interferon pathways.^[9] These findings culminated in the 2011 Nobel Prize in Physiology or Medicine awarded to Bruce Beutler and Jules Hoffmann for their contributions to Toll and TLR discoveries, underscoring PRRs' foundational role in innate immunity. The identification of PRRs marked a paradigm shift, redirecting immunological research from adaptive T- and B-cell responses to the innate system's rapid, pattern-based microbial sensing, with NLRs linking to inflammasome activation and RLRs/cGAS integrating with interferon signaling by the mid-2010s.^[10] As of 2025, ongoing research continues to elucidate PRR functions in recognizing damage-associated molecular patterns (DAMPs) in sterile inflammation and advances therapeutic targeting of PRRs for immune modulation in diseases like autoimmunity and cancer.^[11]

PRR families in animals

Toll-like receptors (TLRs)

Toll-like receptors (TLRs) represent a major family of membrane-bound pattern recognition receptors (PRRs) in animals, pivotal for detecting microbial components and initiating innate immune responses. These type I transmembrane glycoproteins are characterized by a modular architecture: an extracellular ligand-binding domain composed of multiple leucine-rich repeats (LRRs) that form a horseshoe-shaped solenoid structure, a single spanning transmembrane helix, and an intracellular Toll/interleukin-1 receptor (TIR) domain responsible for signal propagation. The LRR ectodomain, typically comprising 16–28 repeats, enables specific recognition of diverse pathogen-associated molecular patterns (PAMPs) through concave or convex surfaces that interact with ligands. This structural motif allows flexibility in binding various molecular shapes while maintaining specificity.^[12] In humans, there are ten functional TLRs (TLR1–10), encoded by genes clustered on chromosomes 4 and X. Their subcellular localization is tightly regulated to match ligand accessibility and prevent aberrant activation by self-molecules. Cell surface TLRs, including TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10, reside on the plasma membrane of various cell types and primarily sense extracellular bacterial and fungal components. In contrast, endosomal TLRs such as TLR3, TLR7, TLR8, and TLR9 are trafficked to intracellular compartments like endosomes and lysosomes, where they detect internalized nucleic acids from viruses or bacteria. This compartmentalization is governed by specific trafficking motifs; for instance, endosomal TLRs contain tyrosine-based motifs that mediate internalization via AP-2 adaptors.^[13]^[14] TLRs exhibit diverse ligand specificities, often requiring accessory proteins for optimal recognition. The following table summarizes key ligands for human TLRs, highlighting their microbial origins:

TLR	Localization	Representative Ligands	Notes
TLR1	Cell surface	Triacyl lipopeptides (e.g., Pam3CSK4 from bacteria)	Forms heterodimers with TLR2^[14]
TLR2	Cell surface	Diacyl lipopeptides (e.g., Pam2CSK4 from Gram-positive bacteria), lipoteichoic acid, zymosan (fungi)	Heterodimerizes with TLR1 or TLR6; recognizes multiple PAMPs^[14]
TLR3	Endosomal	Double-stranded RNA (dsRNA, e.g., from viruses like poly(I:C))	Homodimerizes^[14]
TLR4	Cell surface	Lipopolysaccharide (LPS from Gram-negative bacteria), with MD-2 and LBP co-factors	Forms homodimers; also senses viral proteins like RSV F protein^[14]
TLR5	Cell surface	Flagellin (from bacterial flagella)	Recognizes motile bacteria^[14]
TLR6	Cell surface	Diacyl lipopeptides (e.g., from mycoplasma), fungal zymosan	Heterodimerizes with TLR2^[14]
TLR7	Endosomal	Single-stranded RNA (ssRNA, e.g., from viruses like imiquimod agonists)	Recognizes GU-rich sequences^[14]
TLR8	Endosomal	Single-stranded RNA (ssRNA, e.g., from viruses like loxoribine)	Prefers UG-rich sequences; active in humans and mice^[14]
TLR9	Endosomal	Unmethylated CpG DNA (from bacteria and viruses)	Recognizes bacterial DNA motifs^[14]
TLR10	Cell surface	Microbial components (e.g., from Listeria monocytogenes, Streptococcus pneumoniae), HIV gp41, dsRNA	Least characterized; acts as anti-inflammatory regulator; interacts with TLR2 ligands^[15]^[13]

Upon ligand engagement, TLRs typically dimerize—either as homodimers (e.g., TLR4) or heterodimers (e.g., TLR2/TLR1)—inducing conformational changes that bring TIR domains into proximity to recruit signaling molecules. The TIR domain briefly facilitates initiation of intracellular signaling cascades.^[13] TLRs are expressed across a wide range of cells, including professional immune cells like macrophages, dendritic cells, and B cells, as well as non-immune cells such as epithelial cells, endothelial cells, and fibroblasts, enabling surveillance at barrier sites and within tissues. This broad expression pattern supports both pathogen detection and homeostasis. Evolutionarily, TLRs trace back to the fruit fly Drosophila melanogaster, where the Toll receptor first demonstrated antimicrobial defense, underscoring their ancient conservation across metazoans. Notably, certain TLRs, such as TLR2, also contribute to symbiotic interactions by recognizing harmless commensal microbes, for instance, in the gut microbiota where they promote tolerance to bacterial lipoproteins from Bacteroides species.^[13]

C-type lectin receptors (CLRs)

C-type lectin receptors (CLRs) are a diverse family of pattern recognition receptors that primarily recognize glycan structures on pathogens and host cells, playing crucial roles in innate immunity through extracellular sensing. These receptors are characterized by the presence of one or more C-type lectin-like domains (CTLDs), which enable calcium-dependent binding to carbohydrates. CLRs can function as membrane-bound or soluble proteins, but this section focuses on their membrane-associated forms specialized for detecting fungal components and self-glycans.^[16]^[17] The core structural feature of CLRs is the CTLD, a compact globular domain stabilized by disulfide bridges and containing specific motifs for ligand binding, such as EPN for mannose or QPD for galactose recognition in a Ca²⁺-dependent manner. Membrane-bound CLRs are classified into type I and type II transmembrane proteins based on their orientation: type I CLRs, like the mannose receptor (MR), have an extracellular N-terminus with multiple CTLDs and a single transmembrane domain, facilitating endocytic functions; in contrast, type II CLRs, such as dectin-1, feature a short N-terminal cytoplasmic tail and an extracellular C-terminal CTLD, often involved in signaling and phagocytosis. This structural diversity allows CLRs to tether pathogens to immune cells or mediate clearance of glycosylated molecules.^[17] CLRs are grouped into families based on phylogeny and function. The mannose receptor family (group I CLRs) includes endocytic receptors like MR (CD206) and DEC-205 (LY75), which recognize mannose and fucose residues on microbial surfaces, promoting pathogen uptake in macrophages and dendritic cells (DCs). The asialoglycoprotein receptor family (group II CLRs) comprises liver-specific receptors such as the asialoglycoprotein receptor (ASGR), which clears desialylated glycoproteins from circulation, maintaining homeostasis. Additional key subtypes include dectin-1 (CLEC7A) and dectin-2 (CLEC6A), which are type II CLRs specialized for fungal cell wall components, with dectin-1 binding β-1,3-glucans and dectin-2 targeting α-mannans.^[16]^[17] Representative ligands for CLRs include fungal polysaccharides such as β-1,3-glucans bound by dectin-1, mannans recognized by the mannose receptor, and α-mannose structures engaged by DC-SIGN (CD209), a group II CLR on DCs that facilitates viral and bacterial adhesion. CLRs also interact with damage-associated molecular patterns (DAMPs), including galectin and vimentin released from damaged cells, linking infection responses to sterile inflammation. These glycan-specific interactions distinguish CLRs from other PRRs by emphasizing carbohydrate motifs over lipids or nucleic acids.^[17] CLRs are predominantly expressed on myeloid cells, including macrophages, DCs, and neutrophils, where they drive endocytosis and phagocytosis of glycan-coated pathogens, enhancing antigen presentation. For instance, the mannose receptor mediates uptake of mycobacterial mannoproteins, while dectin-1 promotes fungal phagocytosis. Beyond immunity, CLRs exhibit dual roles in homeostasis, such as DC-SIGN inducing T-cell tolerance to self-antigens, thereby preventing autoimmunity. These receptors briefly activate pathways like Syk or CARD9 upon ligand binding to coordinate responses.^[17] A unique aspect of the CLR superfamily is its expansion in the human genome, with approximately 100 genes encoding CTLD-containing proteins, reflecting evolutionary adaptation to diverse glycan threats.^[18] Additionally, CLR cross-reactivity with self-glycans contributes to allergic diseases; for example, dectin-1 and DC-SIGN bind similar motifs on house dust mite and peanut allergens, promoting Th2-biased responses that exacerbate hypersensitivity. This glycan mimicry underscores the receptors' role in balancing protective immunity against pathological reactions.^[19]

NOD-like receptors (NLRs)

NOD-like receptors (NLRs) are a family of intracellular pattern recognition receptors that detect microbial motifs and damage-associated molecular patterns in the cytosol of host cells, playing a crucial role in innate immunity against bacterial infections.^[20] In humans, there are approximately 22-23 NLR proteins, which are primarily expressed in immune cells such as macrophages and epithelial cells, with some members showing tissue-specific distribution like NOD1 in intestinal epithelia.^[1] These receptors enable the recognition of intracellular pathogens that evade extracellular sensors, contributing to the maintenance of homeostasis with the gut microbiota.^[20] The canonical structure of NLRs is tripartite, consisting of an N-terminal effector domain for downstream signaling, a central NACHT (domain present in NAIP, CIITA, HET-E, and TP1) oligomerization domain that binds nucleotides, and a C-terminal leucine-rich repeat (LRR) domain responsible for ligand recognition and autoregulation.^[1] The N-terminal effector domains vary across members and include pyrin (PYD), caspase activation and recruitment (CARD), or baculovirus inhibitor of apoptosis repeat (BIR) domains, which facilitate interactions with adaptor proteins.^[20] In the resting state, the LRR domain maintains an autoinhibited conformation; upon ligand binding, it induces a conformational change that promotes NACHT-mediated self-oligomerization, enabling signal transduction.^[1] NLRs are classified into subfamilies based on their N-terminal domains: the NLRC subfamily includes NOD1 and NOD2, which possess CARD domains and sense bacterial peptidoglycans; the NLRP subfamily, with 14 members in humans featuring PYD domains, is involved in inflammasome assembly; and the NAIP subfamily, with one member in humans (NAIP), contains BIR domains and recognizes bacterial proteins such as flagellin.^[20] Other subfamilies like NLRB, NLRA, and NLRX exist but are less characterized in humans.^[1] Representative ligands include γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) for NOD1, derived from Gram-negative bacterial peptidoglycan; muramyldipeptide (MDP) for NOD2, a motif common to both Gram-positive and Gram-negative bacteria; and for NLRP3, diverse stimuli such as extracellular ATP, monosodium urate (uric acid) crystals, and the bacterial toxin nigericin, which trigger potassium efflux.^[1]^[21] NLRs are ubiquitously expressed but enriched in barrier tissues like the intestinal epithelium and professional phagocytes such as macrophages, where they monitor cytosolic contents for invasive microbes.^[20] Activation leads to oligomerization and recruitment of adaptor molecules, with some NLRPs briefly assembling inflammasomes to activate caspase-1 for inflammatory responses.^[1] Notably, NOD1 and NOD2 play a key role in sensing the gut microbiota by detecting peptidoglycan fragments that breach the epithelial barrier, helping to regulate microbial composition and prevent dysbiosis.^[20] Mutations in NOD2, such as the frameshift 3020insC variant, are strongly associated with increased susceptibility to Crohn's disease, impairing bacterial recognition and leading to chronic inflammation.^[22]

RIG-I-like receptors (RLRs)

RIG-I-like receptors (RLRs) are a family of cytoplasmic pattern recognition receptors that detect viral RNA in the cytosol, playing a crucial role in initiating antiviral innate immune responses. These receptors belong to the DExD/H-box helicase family and are characterized by their ability to recognize specific structural features of non-self RNA, distinguishing them from host RNAs. RLRs are essential for establishing an antiviral state in infected cells, primarily through the induction of type I interferons, though their downstream signaling is mediated via the adaptor protein MAVS to activate interferon regulatory factors.^[23] The core structure of RLRs includes a central DExD/H-box helicase domain responsible for ATP-dependent RNA binding and unwinding, flanked by an N-terminal domain containing caspase activation and recruitment (CARD) motifs in most members and a C-terminal regulatory domain (CTD) that facilitates autoregulation. The helicase domain consists of two RecA-like subdomains (Hel1 and Hel2) that hydrolyze ATP to translocate along RNA, enabling conformational changes upon ligand recognition. The CTD, often featuring a zinc-binding motif, serves as a sensor for RNA ligands while maintaining the receptor in an autoinhibited state by masking the CARD domains, preventing spurious activation.^[24]^[25] The RLR family comprises three main members: retinoic acid-inducible gene I (RIG-I, encoded by DDX58), melanoma differentiation-associated protein 5 (MDA5, encoded by IFIH1), and laboratory of genetics and physiology 2 (LGP2, encoded by DHX58). RIG-I preferentially recognizes short double-stranded RNA (dsRNA) molecules bearing a 5'-triphosphate (5' PPP) end or blunt ends, such as the panhandle structures generated during influenza A virus replication. In contrast, MDA5 detects longer dsRNA (>1 kb), including replicative intermediates from viruses like encephalomyocarditis virus (EMCV), a picornavirus. LGP2, lacking CARD domains, acts primarily as a regulatory protein that binds dsRNA termini and modulates the activity of RIG-I and MDA5 without direct signaling capability. These receptors discriminate viral from host RNA through features like the uncapped 5' PPP on viral genomes—absent in capped or 2'-O-methylated host mRNAs—and RNA length or secondary structure, ensuring specificity.^[26] RLRs are broadly expressed at low basal levels in most cell types, including epithelial cells and immune cells like macrophages and dendritic cells, but their expression is rapidly upregulated following viral infection or type I interferon stimulation. Activation requires ATP hydrolysis for RNA unwinding, which induces a conformational shift: in RIG-I, ligand binding to the CTD releases the autoinhibitory latch, exposing CARDs for oligomerization; MDA5 forms polar filaments along long dsRNA scaffolds. This auto-regulation via CTD masking of CARDs prevents aberrant activation by self-RNA, highlighting a key unique aspect of RLRs in maintaining immune homeostasis while mounting robust antiviral responses. LGP2's regulatory role further fine-tunes this process, either enhancing or dampening RLR signaling depending on the viral context.^[25]^[24]^[23]

AIM2-like receptors (ALRs)

AIM2-like receptors (ALRs) are a family of cytoplasmic pattern recognition receptors characterized by their ability to detect double-stranded DNA (dsDNA) and initiate inflammasome assembly. These receptors typically feature a bipartite domain organization, consisting of an N-terminal pyrin domain (PYD) that facilitates homotypic interactions for inflammasome formation and a C-terminal hematopoietic expression/interferon-inducible nature (HIN) domain responsible for nucleic acid binding. The HIN domain engages dsDNA through electrostatic interactions within positively charged surface grooves, enabling sequence-independent recognition of microbial or self-derived DNA.^[27]^[28] Prominent members of the ALR family include absent in melanoma 2 (AIM2), which senses cytosolic dsDNA from viruses and bacteria, and interferon-inducible protein 16 (IFI16), which also detects dsDNA and can activate the STING pathway in addition to inflammasome signaling. In humans, the ALR family comprises four members: AIM2, IFI16, myeloid nuclear differentiation antigen (MNDA), and interferon-inducible protein X (IFIX or PYHIN1). Key ligands for AIM2 include synthetic dsDNA analogs like poly(dA:dT) and viral DNA such as that from herpes simplex virus 1 (HSV-1), with binding affinity being length-dependent—optimal activation occurs with dsDNA longer than 70 base pairs, though shorter fragments (around 24 base pairs) can initiate interactions.^[29]^[30]^[31]^[32]^[33] ALRs are broadly expressed across immune and non-immune cells, with expression levels upregulated by type I interferons during infection or inflammation. Upon ligand binding, ALRs undergo oligomerization along DNA scaffolds, forming filamentous assemblies that amplify signaling through PYD-mediated recruitment of adaptor proteins. This process underpins the role of the AIM2 inflammasome in inducing pyroptosis as a defense mechanism against intracellular pathogens. Unlike in mice, which possess up to 13 ALRs, the more limited human repertoire highlights species-specific adaptations in DNA sensing.^[34]^[28]^[35]

Cyclic GMP-AMP synthase (cGAS) and STING

Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) form a key cytosolic pathway for detecting double-stranded DNA (dsDNA), serving as a major surveillance system independent of membrane-bound pattern recognition receptors. This axis enables cells to sense foreign microbial DNA or misplaced self-DNA, initiating innate immune responses through the production of second messengers. Unlike other DNA sensors such as AIM2-like receptors (ALRs), which directly trigger inflammasomes, the cGAS-STING pathway emphasizes the synthesis of cyclic dinucleotides to amplify signaling. cGAS is a soluble enzyme characterized by its Mab21 domain, which facilitates dsDNA binding in a sequence-independent manner. The domain enables a 2:1 stoichiometry of cGAS molecules to one dsDNA segment, preferentially engaging lengths greater than 40 base pairs to induce conformational changes and enzymatic activation. Upon binding, cGAS exhibits nucleotidyltransferase activity, catalyzing the conversion of ATP and GTP into the second messenger 2'3'-cyclic GMP-AMP (2'3'-cGAMP). This non-canonical cyclic dinucleotide binds with high affinity to downstream effectors, distinguishing it from bacterial cyclic di-GMP or di-AMP. STING is a transmembrane protein localized to the endoplasmic reticulum (ER), featuring four transmembrane helices and a cytosolic C-terminal tail that includes a TBK1-binding domain. As a cyclic dinucleotide sensor, STING oligomerizes upon ligand engagement, adopting a conformation that exposes interaction sites for signaling partners. The C-terminal domain's structural plasticity allows it to detect 2'3'-cGAMP with specificity, triggering conformational rearrangements essential for pathway propagation. Ligands for this pathway include microbial dsDNA from viruses or bacteria, as well as endogenous sources such as leaked mitochondrial DNA (mtDNA) during cellular stress or damage. mtDNA, resembling bacterial DNA due to its circular and unmethylated nature, can escape into the cytosol and activate cGAS, highlighting the pathway's role in sterile inflammation. 2'3'-cGAMP acts as the primary second messenger, diffusing within cells or even transferring via gap junctions to neighboring cells. Activation begins with dsDNA binding to cGAS, forming a complex that allosterically unlocks its catalytic site to synthesize 2'3'-cGAMP. This second messenger then binds STING in the ER, inducing its oligomerization and subsequent trafficking to the Golgi apparatus via the COPII pathway. At the Golgi, STING recruits TBK1 through its C-terminal domain, positioning the complex for further interactions while undergoing palmitoylation for stability. Human STING exhibits substantial genetic diversity, with approximately 30% of the population carrying non-reference alleles such as the common HAQ haplotype (R71H-G230A-R293Q), which can modulate ligand sensitivity and signaling efficiency. Gain-of-function mutations in STING, such as those causing STING-associated vasculopathy with onset in infancy (SAVI), lead to constitutive pathway activation and autoinflammatory conditions characterized by vasculopathy, interstitial lung disease, and elevated type I interferon signatures. These variants underscore the pathway's delicate balance in preventing autoimmunity while mounting defenses against pathogens.

Secreted PRRs

Secreted pattern recognition receptors (PRRs), also known as humoral or soluble PRRs, are soluble proteins that circulate in extracellular fluids such as serum and mucosal secretions, enabling early detection and neutralization of pathogens before they interact with cellular receptors.^[36] These molecules primarily function by recognizing conserved microbial patterns in the extracellular space, facilitating opsonization for phagocytosis, activation of the complement system via the lectin pathway, and aggregation of pathogens to limit their spread.^[37] Unlike membrane-bound PRRs, secreted PRRs operate in the humoral arm of innate immunity, providing a first line of defense in body fluids.^[2] Collectins represent a major family of secreted PRRs, characterized by their collagen-like domains and C-type lectin-like carbohydrate recognition domains (CRDs) that enable calcium-dependent binding to sugars.^[36] Mannose-binding lectin (MBL), a prototypical collectin, is produced in the liver and circulates in serum as oligomers of three polypeptide chains, each featuring an N-terminal cysteine-rich region, a collagen-like segment, an α-helical neck, and a C-terminal CRD.^[2] MBL binds to microbial carbohydrates such as mannose, fucose, and N-acetylglucosamine on bacteria, fungi, and parasites, promoting opsonization by enhancing pathogen uptake via phagocytes and activating complement through association with MBL-associated serine proteases (MASPs).^[37] Other collectins include surfactant proteins A (SP-A) and D (SP-D), which are synthesized by alveolar type II and Clara cells in the lungs, where they target similar carbohydrate ligands on respiratory pathogens like Aspergillus fumigatus and house dust mites, aiding aggregation and clearance in mucosal surfaces.^[36] MBL deficiency, affecting up to 25% of certain populations with serum levels below 500 ng/ml, is associated with increased susceptibility to infections, underscoring its role in immune homeostasis.^[36] Ficolins, another class of secreted PRRs, share structural similarities with collectins, featuring collagen-like domains but with fibrinogen-like recognition domains instead of CRDs, allowing binding to acetylated compounds.^[2] In humans, three ficolins exist: ficolin-1 (M-ficolin), ficolin-2 (L-ficolin, liver-produced), and ficolin-3 (H-ficolin, expressed in airways and liver).^[37] These oligomers recognize ligands such as N-acetylglucosamine and lipoteichoic acid on Gram-positive bacteria, facilitating opsonization and complement activation via the lectin pathway in a manner analogous to MBL.^[36] Ficolins often form complexes with MBL or collectins to amplify immune responses, and deficiencies in ficolin-2 have been linked to heightened risks of allergic and infectious diseases.^[37] Pentraxins, the third key family, are multimeric proteins defined by a conserved C-terminal pentraxin domain, existing as short (e.g., C-reactive protein, CRP) or long (e.g., PTX3) forms.^[36] CRP, an acute-phase protein synthesized in the liver, assembles into a pentameric disc structure that binds phosphocholine on bacterial surfaces and damaged cells, promoting opsonization, complement fixation via C1q, and pathogen aggregation during inflammation.^[2] PTX3, produced by immune cells like monocytes and endothelial cells rather than the liver, forms octamers with an extended N-terminal domain and recognizes fungal carbohydrates, bacterial lipids, and damage-associated molecular patterns (DAMPs) such as chromatin from necrotic cells.^[37] Both pentraxins elevate during infection—CRP serum levels can rise from baseline to over 100 mg/L, while PTX3 increases from ~2 ng/ml to 200-800 ng/ml—and genetic variants in PTX3 are associated with severe infections like aspergillosis.^[36] Collectins and ficolins exhibit evolutionary conservation as precursors to C-type lectin receptors (CLRs), sharing domain architectures that bridge soluble and membrane-bound pathogen recognition.^[36] These secreted PRRs coordinate briefly with membrane PRRs like CLRs by opsonizing pathogens for enhanced cellular uptake.^[2]

PRRs in plants

Receptor-like kinases (RLKs)

Receptor-like kinases (RLKs) are a major class of plasma membrane-localized pattern recognition receptors (PRRs) in plants, enabling the direct perception of microbial patterns and initiation of immune signaling. These transmembrane proteins typically feature an extracellular ligand-binding domain, a single transmembrane helix, and an intracellular serine/threonine kinase domain that transduces signals upon activation. The extracellular domains often consist of leucine-rich repeats (LRRs) for recognizing diverse pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), while some RLKs, such as those in the LysM family, bind carbohydrate ligands like chitin. In Arabidopsis thaliana, the RLK family comprises over 600 members, representing approximately 2.5% of the protein-coding genes, with many implicated in immunity.^[38]^[39] Prominent examples of immune RLKs include FLAGELLIN SENSING 2 (FLS2), which detects the bacterial flagellin-derived peptide flg22—a conserved 22-amino-acid epitope that elicits pattern-triggered immunity (PTI). Similarly, ELONGATION FACTOR TU RECEPTOR (EFR) recognizes elf18, an 18-amino-acid peptide from the bacterial elongation factor Tu (EF-Tu), triggering defense responses against bacterial invaders. For fungal pathogens, CHITIN ELICITOR RECEPTOR KINASE 1 (CERK1), a LysM-RLK, binds chitin oligomers (typically 4-8 units in length) derived from fungal cell walls, essential for chitin-induced immunity in Arabidopsis. These RLKs often function through heteromerization with co-receptors, such as BRI1-ASSOCIATED KINASE 1 (BAK1/SERK3), which enhances ligand binding and downstream phosphorylation events.00261-5.pdf)^[40]^[39] Upon ligand perception, RLKs activate rapid immune responses, including a reactive oxygen species (ROS) burst via respiratory burst oxidase homologs (RBOHs), mitogen-activated protein kinase (MAPK) cascades that amplify signaling, and stomatal closure to restrict pathogen entry. For instance, flg22 binding to FLS2-BAK1 complexes phosphorylates and activates BOTRYTIS-INDUCED KINASE 1 (BIK1), leading to RBOHD-mediated ROS production and MAPK activation within minutes. These responses contribute to PTI, restricting microbial proliferation at the cell surface. A distinctive feature of many immune RLKs, such as FLS2 and EFR, is their classification as non-arginine-aspartate (non-RD) kinases, where a conserved arginine in the activation loop is replaced, conferring resistance to manipulation by pathogen effectors that target RD kinases. This structural adaptation enhances the robustness of plant innate immunity.^[41]00067-5)00612-7)00261-5.pdf)

Receptor-like proteins (RLPs)

Receptor-like proteins (RLPs) are a class of pattern recognition receptors (PRRs) in plants that function as immune sensors at the cell surface, detecting microbial elicitors and initiating defense responses without possessing intrinsic kinase activity.^[42] These proteins are single-pass transmembrane receptors characterized by an extracellular domain for ligand binding, a transmembrane region, and a short intracellular tail lacking a kinase domain, distinguishing them from receptor-like kinases (RLKs).00111-0) The extracellular domains typically feature leucine-rich repeats (LRRs) or, in some cases, malectin-like domains that facilitate recognition of pathogen-derived molecules.^[43] Prominent examples of RLPs include EIX2 from tomato, which binds xylanase elicitors from fungal pathogens to trigger defense signaling; Cf-9, which recognizes the Avr9 effector from the fungus Cladosporium fulvum; and Ve1, which detects the Ave1 effector from the vascular wilt fungus Verticillium dahliae.^[44] These RLPs perceive a range of ligands, such as fungal cell wall fragments, xylanases, and effectors like Pep1 from Verticillium species, enabling the detection of both conserved pathogen-associated molecular patterns (PAMPs) and specific virulence factors.^[45] Upon ligand binding, RLPs initiate pattern-triggered immunity (PTI) by forming heterodimers with co-receptor RLKs, such as SOBIR1, which transduces the signal downstream; this complex often involves additional partners like BAK1 for full activation.^[46] In Arabidopsis thaliana, approximately 57 RLPs have been identified, contributing to both PTI and effector-triggered immunity (ETI), where some RLPs, like those in the Cf family, confer race-specific resistance by directly recognizing pathogen effectors.^[47] Recent engineering efforts have demonstrated the potential of chimeric RLPs to broaden disease resistance; for instance, modifications to the C-terminal domain of RLP23 enhance PTI responses against bacterial pathogens in tomato without yield penalties, while synthetic immune receptor designs incorporating RLP modules confer durable, spectrum-wide protection against fungal and bacterial threats.^[48]^[49]

Signaling pathways

TLR signaling

Toll-like receptor (TLR) signaling is mediated by adapter proteins that transduce signals from the cytoplasmic Toll/interleukin-1 receptor (TIR) domains of activated TLRs, culminating in the activation of transcription factors that drive inflammatory and antiviral responses. Upon ligand-induced dimerization, the TIR domains of TLRs recruit specific adapters, primarily myeloid differentiation primary response 88 (MyD88) or TIR-domain-containing adapter-inducing interferon-β (TRIF), to initiate downstream cascades. These pathways are spatially regulated, with plasma membrane signaling favoring proinflammatory outputs and endosomal trafficking enabling interferon production.^[50]^[51] The MyD88-dependent pathway is utilized by all TLRs except TLR3 and involves TIR-TIR interactions that recruit MyD88, which in turn binds interleukin-1 receptor-associated kinases (IRAKs) via death domains. IRAK4 phosphorylates IRAK1, leading to its ubiquitination and association with TNF receptor-associated factor 6 (TRAF6), a ubiquitin ligase that activates the TAK1 kinase complex. TAK1 then phosphorylates IκB kinase (IKK) and mitogen-activated protein kinase (MAPK) pathways, resulting in nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) translocation to induce proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). This pathway is essential for rapid innate immune activation against bacterial and fungal pathogens.^[52]^[53]^[50] In contrast, the TRIF-dependent pathway is engaged directly by TLR3 or, for TLR4, via the bridging adapter TRIF-related adapter molecule (TRAM). TRIF recruits TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε), which phosphorylate interferon regulatory factor 3 (IRF3), promoting type I interferon (IFN-α/β) expression for antiviral defense. Concurrently, TRIF interacts with receptor-interacting protein 1 (RIP1) and TRAF6 to activate NF-κB via TAK1, amplifying inflammatory gene expression. Crosstalk between MyD88 and TRIF pathways in TLR4 signaling is spatially controlled, with endosomal localization of TLR4-TRAM-TRIF complexes favoring IRF3-driven IFN responses over plasma membrane MyD88 signaling.^[54]^[55]^[50] Downstream of both pathways, MAPK cascades—including p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK)—are activated by TAK1, phosphorylating transcription factors like AP-1 to synergize with NF-κB and IRF3 for coordinated gene expression. Recent advances include 2025 structural studies on TIR domains and mechanisms of biased agonism, where ligands selectively favor MyD88 or TRIF pathways, offering potential for targeted immunomodulation. Negative regulation prevents excessive inflammation, with single immunoglobulin IL-1-related receptor (SIGIRR) acting as a decoy by sequestering MyD88 and IRAKs, and suppression of tumorigenicity 2 (ST2) inhibiting TIR interactions in IL-1R/TLR family signaling.^[53]^[56]^[57]^[58]^[59]

NLR and ALR signaling

NLRs and ALRs form multiprotein complexes known as inflammasomes upon recognition of intracellular pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). In the case of NLRP3, a prominent NLR, ligand-induced oligomerization exposes its pyrin domain (PYD), which recruits the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) through PYD-PYD interactions. ASC then oligomerizes into filaments, recruiting pro-caspase-1 via CARD-CARD interactions, leading to proximity-induced autoproteolysis and generation of active caspase-1. Similarly, for ALRs such as AIM2, double-stranded DNA binding triggers AIM2 oligomerization, directly recruiting ASC through PYD-PYD contacts to form the AIM2 inflammasome, which in turn assembles pro-caspase-1 for activation.^[60]^[61]^[61] Active caspase-1 processes its substrates to drive inflammatory responses. It cleaves the proinflammatory cytokine precursors pro-IL-1β and pro-IL-18 at specific aspartate residues, yielding mature IL-1β and IL-18 that are secreted to amplify innate immunity. Additionally, caspase-1 proteolytically activates gasdermin D (GSDMD) by cleaving its autoinhibitory linker, releasing the N-terminal GSDMD fragment that oligomerizes and forms plasma membrane pores, leading to pyroptosis—an inflammatory form of lytic cell death that releases intracellular contents and enhances pathogen clearance. Pyroptosis is a key outcome of both NLRP3 and AIM2 inflammasomes, distinguishing them from non-lytic immune signaling pathways.^[62]^[62]^[62] NLRP3 activation follows a two-signal model to ensure controlled inflammasome assembly. The priming signal (signal 1), often delivered by Toll-like receptor (TLR) ligands or cytokines, activates NF-κB transcription factor, upregulating NLRP3 and pro-IL-1β expression. The activation signal (signal 2) then triggers NLRP3 oligomerization through diverse mechanisms, including potassium (K+) efflux, reactive oxygen species (ROS) generation, or release of mitochondrial DNA (mtDNA), converging on NEK7 kinase-dependent NLRP3-ASC interactions. This model prevents aberrant activation while responding to a broad array of stimuli, such as crystals, toxins, or metabolic stressors.^[63]^[63]^[63] For ALRs, AIM2 directly integrates with ASC to form a functional inflammasome, as its HIN domain binds dsDNA while the PYD scaffolds ASC recruitment without requiring additional adaptors. IFI16, another ALR, cooperates with AIM2 in certain contexts, such as during cytosolic DNA sensing in viral infections, where IFI16 enhances AIM2 inflammasome assembly by facilitating DNA delivery or stabilizing complexes, though it can also exert regulatory effects. This integration allows ALRs to mount robust responses to nucleic acid threats.^[61] A non-canonical inflammasome pathway, independent of NLRP3 or AIM2, involves human caspase-4 and caspase-5 (or mouse caspase-11), which directly sense cytosolic lipopolysaccharide (LPS) from Gram-negative bacteria via CARD-lipid A interactions. This binding induces caspase oligomerization and autoprocessing, enabling cleavage of GSDMD to form pores and drive pyroptosis, while also indirectly promoting IL-1β release through secondary caspase-1 activation. Unlike canonical pathways, this route can lead to IL-1 secretion without full pyroptosis in some cell types, providing a rapid barrier against intracellular bacterial replication.^[64]^[64]^[64]

RLR and cGAS-STING signaling

Upon activation by viral double-stranded RNA ligands, RIG-I and MDA5 undergo conformational changes that expose their N-terminal CARD domains, enabling direct interaction with the adaptor protein MAVS on the outer mitochondrial membrane or endoplasmic reticulum.^[23] MAVS then oligomerizes into prion-like aggregates, recruiting TRAF3 and TRAF6 to form a signaling complex that activates the kinases TBK1 and IKKε, which in turn phosphorylate and dimerize IRF3 for translocation to the nucleus and induction of IFN-β transcription. This pathway specifically detects short 5'-triphosphorylated RNAs for RIG-I and longer double-stranded RNAs for MDA5, initiating a robust antiviral response. In parallel, the cGAS-STING pathway responds to cytosolic double-stranded DNA from pathogens or damaged cells, where cGAS synthesizes the second messenger 2'3'-cyclic GMP-AMP (cGAMP). cGAMP binding to STING on the endoplasmic reticulum triggers STING polymerization and translocation to perinuclear sites, where it recruits TBK1 to phosphorylate both STING and IRF3, promoting IRF3 dimerization and type I IFN production, while TRAF6 activation leads to NF-κB-mediated proinflammatory cytokine expression.^[65] This mechanism ensures rapid detection of DNA threats, distinct from RNA sensing by RLRs.^[66] Both pathways converge on type I IFN signaling through the IFNAR receptor, which activates JAK1 and TYK2 kinases to phosphorylate STAT1/STAT2, forming a complex with IRF9 that drives transcription of interferon-stimulated genes (ISGs) such as MxA and OAS, establishing an antiviral state. Negative feedback is mediated by ISGs like ISG15, which ubiquitinates pathway components to dampen excessive signaling and prevent autoimmunity.^[23] Activation of RLR and cGAS-STING pathways induces not only IFN production but also apoptosis in infected cells via IRF3-mediated upregulation of proapoptotic genes, limiting viral spread. Recent studies highlight metabolic rewiring, including MAVS-dependent upregulation of glycolysis and shifts to the pentose phosphate pathway, supporting energy demands for immune activation.^[67] Crosstalk between RLRs and cGAS-STING enhances responses, as RLR activation promotes mitochondrial DNA release into the cytosol, priming cGAS for amplified IFN production during RNA virus infections.^[68]

CLR signaling

C-type lectin receptors (CLRs) employ distinct signaling pathways to orchestrate antifungal immunity and immune tolerance, primarily through ITAM-like (immunoreceptor tyrosine-based activation motif) and non-ITAM mechanisms. In the ITAM-coupled pathway, exemplified by Dectin-1 and Dectin-2, ligand binding to the receptor's hemITAM motif induces phosphorylation of spleen tyrosine kinase (Syk) by Src family kinases, initiating downstream signaling.^[16] This cascade recruits the adaptor protein CARD9, which complexes with Bcl10 and MALT1 to activate NF-κB, promoting the production of Th17-polarizing cytokines such as IL-17 and IL-22 essential for antifungal defense.^[69] These responses drive T helper 17 cell differentiation and neutrophil recruitment, highlighting the pathway's role in mucosal immunity against fungi like Candida albicans.^[69] In contrast, non-ITAM pathways in CLRs like DC-SIGN mediate anti-inflammatory tolerance. Upon ligand engagement, DC-SIGN activates Raf-1 kinase, which acetylates the NF-κB p65 subunit to upregulate IL-10 production, suppressing excessive inflammation and promoting regulatory T cell responses.^[70] Similarly, the mannose receptor facilitates pathogen endocytosis into lysosomes for degradation without eliciting strong proinflammatory signals, prioritizing clearance over activation in myeloid cells.^[70] CLR signaling yields diverse cellular outcomes tailored to pathogen context. ITAM-coupled CLRs such as Dectin-1 trigger reactive oxygen species (ROS) generation and enhance phagocytosis in macrophages and neutrophils, directly combating fungal invasion.^[71] Activation of mitogen-activated protein kinase (MAPK) pathways, particularly ERK, further supports dendritic cell maturation and antigen presentation.^[71] Group II CLRs, including the asialoglycoprotein receptor (ASGPR), primarily mediate glycoprotein clearance via endocytosis with minimal inflammatory signaling, focusing on homeostasis rather than immunity.^[69] Regulation of CLR signaling ensures balanced responses, with unique mechanisms targeting key components. Fungal pathogens deploy phosphatases to inhibit Syk activity, dampening host defenses and facilitating infection persistence.^[71] Recent 2025 research reveals epigenetic modifications, such as histone acetylation induced by CLR activation, in the context of trained immunity.^[72] CLR pathways also exhibit crosstalk with Toll-like receptors (TLRs) to amplify adaptive immunity. For instance, Dectin-2 synergizes with TLRs to boost IL-12 and IFN-γ production, enhancing Th1 responses against fungi while integrating antifungal and bacterial signals.^[69]

Regulation of PRR activity

Positive regulation

Positive regulation of pattern recognition receptors (PRRs) involves multiple mechanisms that enhance their sensitivity, activation, and downstream signaling to amplify innate immune responses. Post-translational modifications play a central role in this process. For instance, K63-linked ubiquitination of TNF receptor-associated factor 6 (TRAF6) occurs through its auto-ubiquitination, which is essential for activating downstream pathways in Toll-like receptor (TLR) signaling, thereby promoting NF-κB and MAPK activation. Similarly, tripartite motif-containing protein 25 (TRIM25) mediates K63-linked ubiquitination of the CARD domains of retinoic acid-inducible gene I (RIG-I), facilitating its oligomerization and interaction with mitochondrial antiviral-signaling protein (MAVS) to induce type I interferon production. Phosphorylation events also contribute, such as the autophosphorylation of interleukin-1 receptor-associated kinase 4 (IRAK4) upon recruitment to the MyD88 complex in TLR signaling, which enables subsequent phosphorylation of IRAK1 and amplification of inflammatory responses. Co-factors further potentiate PRR function by aiding ligand binding and complex assembly. In mammals, lipopolysaccharide-binding protein (LBP) extracts lipopolysaccharide (LPS) from bacterial membranes and transfers it to CD14, which then delivers it to the MD-2/TLR4 complex, enhancing LPS recognition and TLR4 dimerization for robust signaling. In plants, BAK1 (BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED RECEPTOR KINASE 1) acts as a co-receptor for receptor-like kinases (RLKs), while SUPPRESSOR OF BIR1-1 (SOBIR1) stabilizes receptor-like protein (RLP) complexes, both promoting phosphorylation cascades that initiate pattern-triggered immunity (PTI). Priming mechanisms transcriptionally and epigenetically upregulate PRR expression or components to heighten responsiveness. Activation of NF-κB by TLRs induces transcriptional upregulation of NLRP3, priming the inflammasome for subsequent activation by danger signals. Epigenetic modifications, such as histone acetylation at interferon (IFN) promoters following cGAS-STING activation, facilitate chromatin opening and enhance type I IFN gene transcription, amplifying antiviral responses. Feedback loops sustain and intensify PRR signaling. Autocrine type I IFN signaling upregulates expression of RIG-I-like receptors (RLRs) and cGAS through IFN-stimulated response elements, creating a positive amplification circuit for prolonged innate immunity. Recent studies highlight metabolic regulation, where mTOR nuclear translocation boosts NLRP3 inflammasome assembly by inhibiting STAT1 and enhancing IL-1β processing in macrophages.^[73] In plants, hyperactivation of RD-type kinases, such as receptor-like cytoplasmic kinases (RLCKs), during PTI involves rapid phosphorylation bursts that propagate defense signaling, including reactive oxygen species production and callose deposition.

Negative regulation and tolerance

Negative regulation of pattern recognition receptors (PRRs) is essential to prevent excessive inflammation, maintain immune homeostasis, and avoid tissue damage from overzealous responses to microbial or endogenous ligands. These mechanisms include decoy receptors that sequester ligands or block signaling adaptors, degradative pathways that target PRR components for breakdown, and adaptive tolerance processes that dampen repeated stimulations. In both animals and plants, such controls ensure balanced immunity, with failures leading to pathological conditions like sepsis or autoinflammation.^[2] Decoy receptors serve as inhibitory traps for PRR ligands or signaling intermediates. Single immunoglobulin IL-1-related receptor (SIGIRR), also known as TIR8, acts as a decoy by associating with Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs), disrupting their TIR domain interactions and suppressing downstream NF-κB activation, particularly for TLR4-mediated responses to lipopolysaccharide (LPS).^[74] Similarly, IL-1R2 functions as a soluble or membrane-bound decoy that binds IL-1β without signal transduction, preventing its interaction with signaling-competent IL-1R1. Soluble ectodomains of TLR2 and TLR4, shed from the cell surface, circulate and competitively inhibit ligand binding to membrane-bound receptors, thereby attenuating TLR signaling in systemic inflammation.^[2]^[75] Degradative mechanisms further limit PRR activity through protein turnover and dephosphorylation. K48-linked ubiquitination targets PRR pathway components for proteasomal degradation; for instance, tripartite motif-containing protein 29 (TRIM29) ubiquitinates stimulator of interferon genes (STING) at lysine 370, promoting its degradation and curtailing type I interferon production in the cGAS-STING pathway.^[76] Phosphatases also counteract activation by removing phosphate groups; protein tyrosine phosphatase non-receptor type 6 (PTPN6, or SHP-1) dephosphorylates spleen tyrosine kinase (Syk) in C-type lectin receptor (CLR) signaling, thereby inhibiting downstream spleen tyrosine kinase (Syk)-dependent pathways like CARD9-Bcl10-MALT1 activation.^[2] Tolerance mechanisms induce hyporesponsiveness to repeated PRR stimulation, preserving homeostasis during chronic exposure. Endotoxin tolerance, observed after initial LPS challenge, involves interleukin-1 receptor-associated kinase M (IRAK-M) upregulation, which inhibits IRAK1/4 recruitment to MyD88 in TLR4 signaling, reducing NF-κB and MAPK activation without abolishing pathogen detection. Microbiota-induced tolerance employs A20 (TNFAIP3), a deubiquitinase that removes K63-linked ubiquitin from NLR family proteins like NLRP3, preventing inflammasome assembly and IL-1β release in the gut epithelium to tolerate commensal bacteria.^[2]^[77]^[78] In plants, analogous negative controls modulate PRR responses to prevent growth inhibition from sustained immunity. Receptor-like proteins (RLPs), such as those recognizing fungal chitin, undergo ligand-induced endocytosis via clathrin-mediated pathways, internalizing and degrading the complexes to terminate signaling and allow receptor recycling. Effector-triggered immunity (ETI), mediated by nucleotide-binding leucine-rich repeat receptors (NLRs), features negative feedback loops, including phosphorylation by kinases like BIK1 that balance activation and suppression, ensuring rapid but contained hypersensitive responses without systemic overreaction.^[2] Dysregulation of these inhibitory processes underlies pathological inflammation. Loss of TLR4 negative regulation, such as reduced SIGIRR or IRAK-M expression, exacerbates cytokine storms in sepsis by allowing unchecked MyD88-dependent signaling. Gain-of-function mutations in NLRP3 impair its ubiquitination and degradation, leading to spontaneous inflammasome activation and autoinflammatory syndromes like cryopyrin-associated periodic syndromes (CAPS). Recent studies link metabolic dysregulation to impaired STING inhibition; in obesity, diminished DsbA-L-mediated negative control results in persistent cGAS-STING activation, driving adipose inflammation and insulin resistance.^[1]^[79]^[80]

Evolution of PRRs

Origins and conservation

Pattern recognition receptors (PRRs) trace their origins to prokaryotic precursors, where leucine-rich repeat (LRR) domains function in bacterial defense systems against phages. Bacterial NLR-related proteins, featuring NACHT domains and sensor regions analogous to LRRs, detect phage infections and trigger abortive infection mechanisms to protect host cells. Similarly, Toll/interleukin-1 receptor (TIR) domains in prokaryotic NADase effectors, such as those from Brucella species, hydrolyze NAD+ to disrupt host metabolism during pathogenesis, highlighting enzymatic roles predating eukaryotic immunity. These domains predate the prokaryote-eukaryote divergence, with LRR and nucleotide-binding site (NBS) motifs evident in ancient bacterial genomes.^[81]^[82]^[83] In early eukaryotes like fungi and protists, PRR-like systems emerge with conserved motifs. The amoebozoan Dictyostelium discoideum employs TirA, a TIR domain-containing protein homologous to Toll-like receptors (TLRs), to recognize bacterial lipopolysaccharide (LPS) and enhance bactericidal activity via MAPK signaling. NACHT domains, central to NLR function, are also conserved in choanoflagellates, the closest unicellular relatives to animals, where they pair with LRRs in proteins potentially involved in self/non-self discrimination, indicating pre-metazoan origins of cytosolic PRR architecture. These findings suggest PRR components evolved in unicellular eukaryotes for microbial sensing before multicellularity.^[84]^[85] Invertebrate PRRs build on these foundations, with conserved yet simplified repertoires. Drosophila melanogaster features a single TLR ortholog, the Toll receptor, which detects fungal and Gram-positive bacterial patterns to activate antimicrobial peptide production. Instead of canonical NLRs, Drosophila possesses 13 peptidoglycan recognition protein (PGRP) genes encoding LRR-containing sensors that recognize bacterial cell wall components and initiate immune signaling. Caenorhabditis elegans lacks TLRs but expresses a large family of C-type lectin receptors (CLRs), which bind microbial glycans to modulate innate defenses and pathogen avoidance. Common downstream pathways include NF-κB homologs like Relish in Drosophila, which regulates humoral immunity, and interferon (IFN)-like molecules such as Vago in mosquitoes, a secreted cytokine that restricts viral replication via JAK-STAT signaling.^[86]^[87]^[88] PRR diversification accelerated around 600 million years ago (Mya), coinciding with the emergence of multicellularity in eukaryotes during the Ediacaran period, enabling coordinated immune responses in complex organisms. Recent phylogenomic analyses, including those from 2025, reveal horizontal gene transfer (HGT) as a key driver in plant PRR evolution, with microbial-to-plant transfers contributing to the origins of land plant immune receptors like LRR-RLKs during streptophyte diversification. In vertebrates, PRR families underwent further expansion, adapting to diverse pathogens.^[89]^[90]^[91]

Diversification in metazoans and plants

In metazoans, the diversification of pattern recognition receptors (PRRs) has been marked by extensive gene duplication events, particularly in vertebrates. Toll-like receptors (TLRs), for instance, expanded from a single ortholog in invertebrates like Drosophila melanogaster to 10 functional TLRs in humans, driven by tandem and whole-genome duplications that allowed specialization for diverse microbial ligands.^[92] Similarly, NOD-like receptors (NLRs) underwent a dramatic expansion post-chordate divergence, with teleost fish harboring approximately 30–400 NLR genes compared to 22–33 in mammals, reflecting lineage-specific adaptations to aquatic pathogens.^[93] AIM2-like receptors (ALRs) are absent in fish and emerged later in mammalian evolution, whereas RIG-I-like receptors (RLRs) originated early in vertebrate evolution and are present across jawed and jawless vertebrates, including non-teleost fish, to enhance intracellular sensing of viral and bacterial nucleic acids.^[94]^[95]^[96] In plants, PRR repertoires radiated prominently during the transition to land, with receptor-like kinases (RLKs) expanding to over 600 in Arabidopsis thaliana—contrasting with only a handful in algal ancestors—through serial duplications that enabled perception of environmental cues.^[97] Receptor-like proteins (RLPs), numbering around 50 in Arabidopsis, co-evolved with RLKs to form ligand-binding complexes, while LysM-domain RLKs specialized for fungal symbiosis, recognizing chitin and Nod factors in a manner predating angiosperm diversification.^[98] Non-arginine-aspartate (non-RD) kinases, a hallmark of plant immunity, uniquely evolved within RLK signaling to bypass autoinhibition and trigger rapid defense responses, distinguishing them from RD kinases in other contexts.^[99] These expansions were propelled by gene duplication, domain shuffling, and pathogen-driven selection. In plants, TIR-NB-LRR domains shuffled via unequal recombination to generate resistance (R) genes, enhancing effector recognition amid co-evolutionary arms races.^[100] In animals, pathogen pressure, particularly from viruses, accelerated diversification of intracellular sensors like RLRs, with positive selection on RNA-binding domains to counter evolving viral evasion strategies.^[101] Comparatively, metazoan PRRs emphasize intracellular surveillance, with NLRs and RLRs detecting endocytosed threats in the cytosol, whereas plants prioritize extracellular RLKs for immediate cell wall contact with microbes, reflecting sessile lifestyles and mobility differences.^[102] Recent synthetic biology efforts in 2025 have engineered convergent PRRs across kingdoms, demonstrating how modular designs can recapitulate natural diversification for broad-spectrum immunity.^[48]

Clinical and therapeutic implications

Role in infectious diseases

Pattern recognition receptors (PRRs) play a critical role in host defense against infectious diseases by detecting microbial patterns and initiating immune responses. Dysregulation of PRR function, either through genetic deficiencies or pathogen-mediated interference, significantly impacts susceptibility to infections. For instance, polymorphisms in the TLR4 gene, such as Asp299Gly and Thr399Ile, have been associated with hyporesponsiveness to lipopolysaccharide (LPS), leading to increased risk of Gram-negative bacterial sepsis.^[103] Similarly, variants in the NOD2 gene, including the Arg587Arg single nucleotide polymorphism, have been associated with heightened susceptibility to pulmonary tuberculosis in certain populations, such as the Chinese Han, by impairing recognition of muramyl dipeptide from Mycobacterium tuberculosis, thereby reducing NF-κB activation and cytokine production.^[104] These deficiencies highlight how PRR impairments compromise innate immunity, allowing pathogens to establish persistent infections. Conversely, hyperactivation of PRRs can exacerbate disease severity through excessive inflammation. In chronic HIV infection, sustained stimulation of endosomal TLR7 and TLR9 by viral nucleic acids contributes to persistent immune activation, driving plasmacytoid dendritic cell dysfunction and ongoing type I interferon production that fuels T-cell exhaustion and disease progression.^[105] During severe COVID-19, overactivation of the NLRP3 inflammasome by SARS-CoV-2 components, such as viroporins and spike protein, triggers a cytokine storm characterized by elevated IL-1β and IL-18 levels, leading to acute respiratory distress and multi-organ failure.^[106] Pathogens have evolved mechanisms to evade PRR detection, further underscoring their role in infectious outcomes. Hepatitis C virus employs its NS3/4A protease to cleave mitochondrial antiviral signaling protein (MAVS), thereby inhibiting RIG-I-mediated type I interferon responses and promoting viral persistence in hepatocytes.^[107] Likewise, Shigella flexneri secretes IpaH ubiquitin ligases, such as IpaH9.8, which target components of the NOD1 signaling pathway, including NEMO, to dampen NF-κB activation and evade peptidoglycan-induced inflammation during epithelial cell invasion.^[108] In plants, analogous PRR dysfunction increases vulnerability to bacterial pathogens. Mutations in the FLS2 receptor-like kinase, which perceives flagellin from bacteria like Ralstonia solanacearum, result in enhanced susceptibility to bacterial wilt disease, as seen in Arabidopsis and soybean mutants that fail to mount effective reactive oxygen species bursts and defense gene expression.^[109] Recent insights into emerging zoonoses, such as the 2022-2025 mpox outbreaks, reveal the cGAS-STING pathway's pivotal role in sensing monkeypox virus DNA, activating type I interferons to limit viral replication in mice and nonhuman primates; disruptions in this pathway correlate with increased pathogenicity, emphasizing PRRs' ongoing relevance in controlling orthopoxvirus infections.^[110]

Involvement in autoimmune and inflammatory disorders

Pattern recognition receptors (PRRs) play a critical role in autoimmune and inflammatory disorders when they are aberrantly activated by endogenous damage-associated molecular patterns (DAMPs), leading to chronic inflammation and loss of self-tolerance.^[1] These self-molecules, released during cellular stress or damage, mimic pathogen-associated molecular patterns (PAMPs) and trigger PRR signaling pathways, resulting in excessive production of pro-inflammatory cytokines such as type I interferons (IFNs) and interleukin-1β (IL-1β).^[1] In autoinflammatory conditions, this activation stems from genetic mutations causing gain-of-function in PRRs or their downstream effectors, while autoimmune diseases often involve environmental or epigenetic factors that prime PRRs for hypersensitivity to self-antigens.^[1] A prominent mechanism involves mitochondrial DNA (mtDNA) acting as a DAMP to activate the cytosolic PRR cyclic GMP-AMP synthase (cGAS) in systemic lupus erythematosus (SLE). Oxidized mtDNA leaks into the cytosol during mitochondrial dysfunction, binding cGAS to produce cGAMP, which activates the STING pathway and induces type I IFN production, exacerbating autoantibody formation and tissue damage in SLE patients.^[111] Similarly, in psoriasis, S100 proteins (e.g., S100A8/A9, also known as calprotectin) serve as DAMPs that bind Toll-like receptor 4 (TLR4) on keratinocytes and immune cells, promoting NF-κB activation and the release of IL-17 and IL-23, which drive epidermal hyperplasia and chronic skin inflammation.^[112] Several monogenic autoinflammatory diseases highlight the direct impact of PRR dysregulation. Cryopyrin-associated periodic syndromes (CAPS), a group of cryopyrinopathies, arise from gain-of-function mutations in the NLR family pyrin domain-containing 3 (NLRP3) gene, leading to constitutive activation of the NLRP3 inflammasome, excessive IL-1β secretion, and recurrent fever, urticaria, and joint pain.^[113] Familial Mediterranean fever (FMF) results from mutations in the MEFV gene encoding pyrin, an NLR-like protein, which hyperactivates the pyrin inflammasome in response to pathogen effectors or cellular stress, causing episodic serositis and amyloidosis due to unchecked IL-1β release. In Aicardi-Goutières syndrome (AGS), deficiency in the exonuclease TREX1 leads to accumulation of cytosolic self-DNA, which activates cGAS-STING signaling, mimicking viral infection and producing high levels of type I IFNs that cause severe encephalopathy and calcifications in infants.^[114] Breakdown of immune tolerance often involves defective negative regulation of PRR pathways. In rheumatoid arthritis (RA), hyperactivity of interleukin-1 receptor-associated kinase 1 (IRAK1), a key adaptor in TLR and IL-1R signaling, amplifies NF-κB and MAPK pathways in synovial fibroblasts and macrophages, sustaining joint inflammation and erosion.^[115] Epigenetic modifications contribute to PRR priming in SLE, enhancing TLR7 and TLR9 expression and lowering the threshold for IFN-α production in response to self-nucleic acids.^[116] An analogous phenomenon occurs in plants, where misfiring of resistance (R) genes—encoding NLR proteins similar to animal PRRs—triggers a hypersensitive response (HR)-like autoimmunity. Gain-of-function mutations in genes like SNC1 lead to inappropriate recognition of self-components, activating salicylic acid-dependent defenses and localized cell death, mirroring DAMP-driven inflammation in metazoans.^[117] Recent insights as of 2025 emphasize PRR-metabolic links in inflammatory bowel disease (IBD), particularly Crohn's disease, where NOD2 mutations impair bacterial sensing, leading to microbiota dysbiosis with reduced Firmicutes and increased Proteobacteria, which perpetuates NOD2-independent PRR activation (e.g., via TLRs) and barrier dysfunction.^[118] This dysbiosis amplifies chronic mucosal inflammation, highlighting NOD2's role in maintaining microbial homeostasis to prevent autoinflammatory flares.^[119]

Applications in immunotherapy and vaccines

Pattern recognition receptor (PRR) agonists have emerged as potent tools in immunotherapy by mimicking pathogen-associated molecular patterns to stimulate innate immune responses, thereby enhancing adaptive immunity against tumors. For instance, monophosphoryl lipid A (MPL), a detoxified derivative of lipopolysaccharide that acts as a TLR4 agonist, is incorporated into the Cervarix vaccine for human papillomavirus (HPV), where it promotes robust antibody responses and long-term protection against cervical cancer precursors.^[120] Similarly, imiquimod, a synthetic TLR7/8 agonist, is FDA-approved for topical treatment of actinic keratosis and basal cell carcinoma, inducing local inflammation and tumor regression through interferon-alpha production and activation of plasmacytoid dendritic cells. In advanced settings, cyclic dinucleotides like ADU-S100 (also known as MIW815), which activate the cGAS-STING pathway, have been evaluated in phase I/II clinical trials for intratumoral injection in solid tumors such as melanoma and breast cancer, demonstrating enhanced T-cell infiltration and partial responses when combined with checkpoint inhibitors.^[121] PRR antagonists, conversely, offer therapeutic value by dampening excessive inflammation in immunopathologies. Monoclonal antibodies targeting TLR4, such as the investigational agent NI-0101, have shown promise in blocking endotoxin-induced cytokine storms in early clinical trials, including phase I studies demonstrating prevention of cytokine release in healthy volunteers challenged with LPS.^[122] For NLRP3 inflammasome inhibition, MCC950, a selective small-molecule antagonist, has demonstrated efficacy in preclinical and early clinical studies for cryopyrin-associated periodic syndromes (CAPS) by preventing IL-1β release and ameliorating autoinflammatory flares, while in gout models, it suppresses urate crystal-induced inflammation without broad immunosuppression.^[123]^[124] In vaccine development, PRR-targeted adjuvants amplify antigen-specific responses, particularly for challenging pathogens. Trehalose-6,6'-dibehenate (TDB), a synthetic glycolipid agonist of the C-type lectin receptor (CLR) Mincle, is formulated in the CAF01 adjuvant system for tuberculosis (TB) vaccines, where it induces Th1/Th17 polarization and sustained CD4+ T-cell memory in preclinical models and ongoing phase II trials.^[125] Likewise, polyinosinic:polycytidylic acid (poly I:C), a mimic of viral double-stranded RNA that engages RIG-I-like receptors (RLRs) and TLR3, serves as an adjuvant in influenza vaccines, boosting cross-protective humoral and cellular immunity in human trials by promoting type I interferon secretion and dendritic cell maturation.^[126] Beyond human applications, engineered PRRs hold potential in agriculture and emerging vaccine technologies. In plants, receptor-like kinases (RLKs), a class of PRRs, have been synthetically modified to broaden pathogen recognition; for example, chimeric LRR-RLK constructs engineered in 2025 studies confer enhanced resistance to fungal and bacterial threats in crops like wheat and tomato by integrating multiple ligand-binding domains for improved specificity and immunity activation.^[49] These advancements inspire synthetic biology approaches in vaccine design. As of 2025, STING agonists like cyclic dinucleotides continue to advance in phase III trials for cancer immunotherapy, showing improved response rates in combination therapies.^[127] Despite these advances, PRR-based therapies face significant challenges, including achieving receptor specificity to prevent off-target activation that could trigger autoimmunity, as nonspecific TLR agonism has been linked to systemic inflammatory adverse events in up to 20% of trial participants.^[128] Combination strategies mitigate such risks; for example, pairing TLR9 agonists like CpG oligodeoxynucleotides with PD-1 inhibitors enhances antitumor efficacy in melanoma and non-small cell lung cancer trials by synergistically boosting CD8+ T-cell function while limiting exhaustion, achieving objective response rates of 25-40% in resistant populations.^[129] Ongoing research emphasizes dose optimization and delivery systems, such as nanoparticle encapsulation, to balance potency and safety in clinical translation.

Links to cancer, neurodegeneration, and metabolic diseases

Pattern recognition receptors (PRRs) play dual roles in cancer, with certain pathways promoting tumorigenesis through chronic inflammation while others exert suppressive effects via immune activation. Toll-like receptors 2 and 4 (TLR2 and TLR4) contribute to tumor progression in colorectal cancer by recognizing damage-associated molecular patterns (DAMPs) released from dying cells, leading to NF-κB activation and the production of pro-inflammatory cytokines that foster a tumor-supportive microenvironment. Similarly, the NLRP3 inflammasome drives inflammation in pancreatic cancer, where its activation by tumor-derived factors enhances IL-1β secretion, promoting tumor cell proliferation and immune evasion. In contrast, the STING pathway suppresses tumor growth by sensing cytosolic DNA and inducing type I interferons (IFNs), which activate antitumor immune responses; this mechanism underpins type I IFN-based therapies in various cancers, including melanoma and lung tumors. In neurodegeneration, PRR dysregulation amplifies neuroinflammation and neuronal damage through persistent recognition of misfolded proteins and cellular debris. In Alzheimer's disease, amyloid-β (Aβ) aggregates activate TLR2 and TLR4 on microglia, triggering NF-κB signaling and IL-1β release, which exacerbates plaque formation and synaptic loss. The NLRP3 inflammasome is implicated in Parkinson's disease, where α-synuclein fibrils induce its assembly in microglia, leading to caspase-1 activation, IL-1β maturation, and dopaminergic neuron degeneration; inhibition of NLRP3 reduces α-synuclein aggregates and motor deficits in preclinical models. Chronic cGAS-STING pathway activation contributes to amyotrophic lateral sclerosis (ALS) by detecting mitochondrial DNA released from damaged motor neurons, resulting in type I IFN-driven neuroinflammation and accelerated disease progression. PRRs also link to metabolic diseases by sensing metabolic stressors and microbial signals, perpetuating low-grade inflammation. The NLRP3 inflammasome is central to obesity and type 2 diabetes (T2D), activated by saturated fatty acids in adipose tissue to produce IL-1β, which impairs insulin signaling and promotes β-cell dysfunction; NLRP3-deficient models resist high-fat diet-induced insulin resistance. TLR4 on adipocytes senses free fatty acids during high-fat feeding, initiating NF-κB-mediated inflammation that drives systemic metabolic dysregulation. In non-alcoholic fatty liver disease (NAFLD), PRR activation, including NLRP3 and AIM2 inflammasomes, responds to lipid-derived DAMPs, with epigenetic modifications like miR-204-3p suppression of TLR4 signaling exacerbating hepatic steatosis and fibrosis, as highlighted in recent reviews. Mechanisms underlying these associations involve persistent DAMP signaling and host-microbe interactions. High-mobility group box 1 (HMGB1), a prototypical DAMP, sustains PRR activation in tumors by binding TLR4 and RAGE, promoting NF-κB-driven angiogenesis and metastasis. In metabolic syndrome, the gut microbiota-PRR axis amplifies inflammation, where dysbiosis-derived lipopolysaccharides activate TLR4, contributing to insulin resistance and NAFLD progression via NLRP3 crosstalk. Therapeutically, targeting PRRs holds promise for these conditions. STING agonists, such as cyclic dinucleotides, enhance antitumor immunity in cancer by boosting type I IFN production and T-cell infiltration, with ongoing clinical trials in solid tumors. NLRP3 inhibitors, including MCC950 and OLT1177, show efficacy in preclinical neurodegeneration models by mitigating IL-1β-driven damage in Parkinson's and ALS, and in metabolic trials for T2D and NAFLD by reducing adipose inflammation and improving insulin sensitivity. As of November 2025, OLT1177 is in phase II trials for gout, demonstrating reduced inflammation without affecting uric acid levels.^[130]

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Of note, RLKs form a monophyletic gene family and their origin predates the divergence of plants and animals [13,14], whereas RLPs are less conserved [15,16].Missing: RLR | Show results with:RLR
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Toll-Like Receptor 4 Polymorphisms and Risk of Gram-Negative ...
These polymorphic forms of TLR4 have been associated with an increased incidence of Gram-negative infections and sepsis, and more recently with an increased ...
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NOD2 Polymorphisms and Pulmonary Tuberculosis Susceptibility
The association between NOD2 and tuberculosis (TB) risk has been reported widely, but the results of previous studies remained controversial and ambiguous.
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Immunopathogenesis of Asymptomatic Chronic HIV Infection
SIV leads to pDC activation via TLR7 and TLR9 stimulation with subsequent IFNα production in human and RM PBMC that is markedly attenuated in SMs. This ...<|separator|>
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SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as ...
A cytokine “storm,” which in many cases ends in severe acute respiratory syndrome, fulminant myocarditis and kidney injury.
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Heterologous expression of Arabidopsis FLS2 in Nicotiana ...
GmFLS2 contributes quantitatively to soybean resistance to Ralstonia, since soybean Gmfls2 loss‐of‐function mutants exhibit enhanced bacterial wilt ...
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MPXV infection activates cGAS-STING signaling and IFN-I treatment ...
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May 30, 2024 · This article aims to explore the role of the mtDNA-triggered cGAS-STING pathway and its mechanisms in SLE, with the goal of providing novel ...
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Jun 6, 2023 · S100A8 interacts with TLR4-MD2 complex, enhancing inflammatory response in target cells (122) ( Figure 3 ). Activation of TLR4 signaling pathway ...
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CAPS and NLRP3 - PMC - PubMed Central - NIH
Gain-of-function mutations in NLRP3 in CAPS patients lead to activation of the cryopyrin inflammasome resulting in the inappropriate release of inflammatory ...
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Increasing evidence indicates that plant autoimmunity is in many cases the consequence of the inappropriate activation of cytoplasmic immune sensors.Missing: PRR misfiring
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The Effect of NOD2 on the Microbiota in Crohn's Disease - PMC
Mutations to NOD2 promote low diversity and dysbiosis in the microbiome, leading to impaired mucosal barrier function.
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Gut Microbiome Dysbiosis and Inflammatory Bowel Disease ...
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Pattern recognition receptors: immune targets to enhance cancer ...
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MCC950 in the treatment of NLRP3-mediated inflammatory diseases
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Oct 21, 2020 · The NLRP3 inflammasome inhibitor MCC950 blocked constitutive activation of NLRP3 observed in the PBMCs of CAPS patients.
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SLC3037, a NLRP3 inhibitor blocking NEK7 binding to NLRP3, could be a novel agent against diseases associated with NLRP3 inflammasome activation such as gout.
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Targeting the Mincle and TLR3 receptor using the dual agonist ...
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Selection of adjuvants for vaccines targeting specific pathogens - PMC
Liposomes are used in vaccine formulations against influenza, chlamydia, malaria, and tuberculosis (TB). ... Vaccine adjuvant uses of poly-IC and derivatives.
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Systematic Discovery and Design of Synthetic Immune Receptors in ...
Mar 17, 2025 · We describe a strategy to map the recognition landscape of LRR-RLK-XIIs in plants, paving the way for the discovery of novel PRRs that can be synthetically ...Missing: vaccines | Show results with:vaccines
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Pattern recognition receptors: immune targets to enhance cancer ...
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Toll-like receptor 9 agonists and combination therapies - Nature
Jul 28, 2022 · It has also been shown that inhaled TLR9 agonist administration combined with PD-1 antibody induces CD8+ T cells to become highly functional ...