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CD14

CD14 is a multifunctional glycoprotein and pattern recognition receptor that serves as a key co-receptor in the innate immune system, primarily expressed on the surface of monocytes, macrophages, and neutrophils, where it recognizes and binds pathogen-associated molecular patterns such as lipopolysaccharide (LPS) from Gram-negative bacteria to initiate inflammatory responses.^[1] It exists in two main forms: a membrane-bound isoform (mCD14) anchored to the cell surface via a glycosylphosphatidylinositol (GPI) linkage and a soluble isoform (sCD14) released into circulation, both contributing to immune surveillance and signaling.^[1] The CD14 gene, located on chromosome 5q31.3 in humans (NCBI Gene ID: 929), encodes this 375-amino-acid protein, which is heavily glycosylated and plays a central role in bridging microbial detection to downstream immune activation.^[2]^[3] Structurally, CD14 adopts a compact, bent solenoid conformation consisting of 10 leucine-rich repeats that form a hydrophobic N-terminal pocket ideal for binding lipid moieties of microbial ligands.^[3]^[4] It features two conserved N-glycosylation sites—Asn151 and Asn282—with the former bearing complex glycans that facilitate interactions with lectins like galectin-4, aiding in processes such as monocyte differentiation, while the latter contains oligomannose glycans essential for proper protein folding and secretion.^[3] This glycosylation influences not only stability but also the receptor's ability to traffic ligands and modulate immune cell functions.^[3] Functionally, CD14 enhances the sensitivity of immune cells to LPS by cooperating with lipopolysaccharide-binding protein (LBP) in serum, which extracts monomeric LPS from bacterial membranes; the CD14-LPS-LBP complex then transfers LPS to the Toll-like receptor 4 (TLR4)-MD-2 signaling complex on the cell surface, triggering NF-κB activation and the release of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6.^[1] This interaction activates both MyD88-TIRAP-dependent pathways, leading to rapid inflammation, and TRAM-TRIF-dependent pathways, promoting type I interferon production and adaptive immunity priming.^[1] Beyond LPS, CD14 recognizes other acylated microbial products from Gram-positive bacteria and damage-associated molecular patterns (DAMPs), thereby participating in responses to a broad range of infections, sterile inflammation, and tissue repair.^[5] Dysregulation of CD14 expression or function has been implicated in various human diseases, including sepsis—where elevated sCD14 levels correlate with poor outcomes due to excessive inflammation—and chronic conditions such as cardiovascular disease, metabolic disorders like atherosclerosis and non-alcoholic fatty liver disease, autoimmune disorders, and certain cancers including colorectal and gastric carcinomas, highlighting its dual role in protective immunity and pathological inflammation.^[1]

Molecular Biology

Gene Characteristics

The CD14 gene is located on the long arm of human chromosome 5 at cytogenetic band 5q31.3, spanning approximately 1.97 kb of genomic DNA from positions 140,631,732 to 140,633,701 on the reference genome GRCh38.p14. It consists of three exons, with the coding sequence distributed across these exons to produce a mature mRNA that encodes a 375-amino-acid precursor protein. Multiple transcript variants (up to four) have been identified, all encoding the identical protein isoform, with transcript variant 1 representing the predominant form.^[6] The gene structure includes a proximal promoter region that regulates its tissue-specific expression, particularly in monocytic cells. This promoter contains multiple binding sites for the transcription factor Sp1, which binds to three distinct regions and is essential for basal and monocytic-specific transcription. The major Sp1 binding site at position -110 bp relative to the transcription start site plays a critical role; mutations here significantly reduce promoter activity in myeloid cell lines while having minimal impact in non-myeloid cells.^[7]^[8] The CD14 gene exhibits evolutionary conservation across mammalian species, reflecting its fundamental role in innate immunity. Orthologs are present in diverse mammals, including the mouse (Cd14 gene on chromosome 18), where it shares high sequence similarity in the coding region and functional domains such as leucine-rich repeats. This conservation extends to the broader lipopolysaccharide (LPS) receptor system, involving coordinated interactions with proteins like TLR4 and MD-2, which have been maintained in amniotes for over 320 million years to facilitate pathogen recognition. In silico analyses of CD14 coding sequences from 14 mammalian species reveal leucine-rich repeats as the most conserved structural motif, underscoring adaptive evolution in immune response while preserving core functionality.^[9]^[10]^[11] A notable genetic variation in the CD14 gene is the C-159T single nucleotide polymorphism (rs2569190) in the promoter region, located 159 bp upstream of the major transcription start site. This polymorphism disrupts a putative binding site for the transcription factor Sp1 in the C allele, leading to allele-specific differences in transcriptional efficiency. The T allele is associated with enhanced promoter activity, resulting in higher steady-state mRNA levels and elevated circulating soluble CD14 protein concentrations, which may influence susceptibility to inflammatory and atopic conditions. Population studies have linked the TT genotype to increased risk of atopy and altered immune responses to environmental allergens, highlighting its functional implications in human disease.^[12]^[13]

Protein Structure

CD14 is a glycoprotein encoded by a single gene on chromosome 5q31.3, consisting of 375 amino acids in its precursor form, including a 19-amino-acid N-terminal signal peptide that is cleaved to yield the mature protein.^[14] The mature membrane-bound form (mCD14) spans 356 amino acids and has a calculated molecular weight of approximately 37 kDa for the unglycosylated polypeptide, but post-translational modifications increase its apparent mass to about 55 kDa. In contrast, the soluble isoform (sCD14) typically exhibits a lower apparent molecular weight of around 48-56 kDa, depending on glycosylation and proteolytic processing.^[15]^[16] The three-dimensional structure of human CD14, determined by X-ray crystallography at 2.0 Å resolution for the soluble form (PDB: 4GLP), reveals a monomeric protein adopting a bent solenoid conformation characteristic of leucine-rich repeat (LRR) proteins. This horseshoe-shaped architecture is composed of 11 tandem LRRs, each approximately 20-29 amino acids long, forming a concave β-sheet scaffold that curves into a right-handed solenoid with a central hydrophobic core. The structure spans residues 20-347, featuring an amino-terminal hydrophobic pocket presumed to accommodate lipid moieties of ligands, and the overall fold aligns closely with other LRR family members such as Toll-like receptors, sharing conserved repeat motifs for structural integrity.^[4] Comparisons to related LRR proteins, like TLRs and NLRs, highlight CD14's unique elongated horseshoe without additional domains, emphasizing its role as a soluble or anchored adaptor in immune recognition.^[4] CD14 features two primary N-linked glycosylation sites at Asn132 and Asn261, which contribute to its heterogeneity and functional stability by influencing protein folding, secretion, and resistance to proteolysis. These modifications, along with O-linked glycans, add significant mass and protect against degradation, while also modulating ligand affinity by altering surface charge and conformation. Additionally, the protein contains 16 cysteine residues forming eight intramolecular disulfide bonds (e.g., Cys25-Cys36, Cys34-Cys51, Cys187-Cys217, Cys241-Cys272, and others), which rigidly stabilize the LRR scaffold and maintain the horseshoe topology essential for proper assembly and function.^[14]^[17]^[4] The membrane-bound isoform (mCD14) is anchored to the cell surface via a glycosylphosphatidylinositol (GPI) moiety attached to the C-terminal residue (Ser352) after processing of a hydrophobic tail, enabling its localization on myeloid cells. In contrast, sCD14 arises primarily through phospholipase-mediated cleavage of mCD14 or alternative mRNA splicing that excludes the GPI-anchor signal, resulting in a secreted form lacking the C-terminal 15-20 residues but retaining the core LRR domain for ligand interaction. Full atomic coordinates from crystallographic studies confirm high structural similarity between isoforms, with the soluble form providing a model for the extracellular portion of mCD14.^[14]^[18]

Expression and Regulation

Cellular and Tissue Distribution

CD14 is predominantly expressed on cells of the myeloid lineage, serving as a key surface marker for these populations in the innate immune system. It is highly expressed on monocytes, with nearly all peripheral blood monocytes displaying high levels of membrane-bound CD14, particularly on classical monocytes (CD14++CD16-) that constitute 80-90% of circulating monocytes. Macrophages, derived from monocyte differentiation, also exhibit robust CD14 expression across classical subsets, including pro-inflammatory M1 and anti-inflammatory M2 phenotypes. Dendritic cells, especially those of myeloid origin, similarly show CD14 on their surface, facilitating antigen presentation and pathogen recognition. Expression levels are notably lower on other immune cells such as neutrophils, where CD14 is present but at reduced density compared to monocytes (approximately 3% of monocyte levels based on flow cytometric quantification of ~3,300 vs. ~110,000 surface molecules per cell), and on B cells, with minimal detection in resting states.^[19] Epithelial cells in select tissues, including hepatocytes in the liver, alveolar cells in the lung, and cells in the spleen, display low to moderate CD14 expression, often confirmed through immunohistochemistry revealing sparse positivity in non-myeloid compartments. In contrast, CD14 is absent on T cells and the majority of non-immune cells, underscoring its myeloid-restricted profile in steady-state conditions. In tissues, CD14 distribution aligns with immune surveillance sites, showing elevated presence in the spleen, liver (via Kupffer cells), and lung (via alveolar macrophages), as demonstrated by immunohistochemical staining patterns. It is particularly enriched at inflammatory locales, such as atherosclerotic plaques where CD14+ monocyte-derived macrophages accumulate, comprising a significant proportion of plaque-infiltrating cells (up to 20-30% in advanced lesions per flow cytometry analyses), and on mucosal surfaces like the intestinal epithelium, where CD14+ cells contribute to barrier defense. A soluble form of CD14 (sCD14) circulates in serum and plasma at concentrations of 2-5 μg/mL in healthy individuals, contrasting with the GPI-anchored membrane-bound isoform. This sCD14 arises primarily from proteolytic shedding of surface CD14 by enzymes like phospholipase D or from direct secretion by monocytes and macrophages without the GPI anchor, as evidenced by biochemical assays distinguishing the two forms.

Regulation During Differentiation

CD14 was first identified in the 1980s as a differentiation antigen specific to monocytes using monoclonal antibodies, such as MY4, which recognized a surface glycoprotein on human monocytes and macrophages. This discovery facilitated the use of flow cytometry to distinguish monocyte subsets, notably the classical CD14++CD16- monocytes from intermediate (CD14++CD16+) and non-classical (CD14+CD16++) populations, highlighting CD14's role as a key marker in monocyte maturation.^[20] During monopoiesis in the bone marrow, CD14 expression emerges as a marker in late-stage monocyte precursors, distinguishing committed myeloid cells from earlier progenitors.^[21] This upregulation is induced by cytokines such as macrophage colony-stimulating factor (M-CSF) and interleukin-3 (IL-3), which promote the differentiation of CD34+ hematopoietic progenitors into a homogeneous population of CD14+ monocytes.^[22] Upon differentiation into macrophages, CD14 expression is notably increased on M1 (pro-inflammatory) subsets compared to more modest levels on M2 (anti-inflammatory) subsets, reflecting distinct polarization states. Transcriptional control of CD14 in these cells involves the myeloid transcription factors PU.1 and C/EBP family members, which bind to the CD14 promoter to drive expression during macrophage commitment and polarization.^[23] CD14 expression is further modulated by environmental signals, with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) enhancing it through NF-κB activation, creating a positive feedback loop in innate immune responses. In contrast, glucocorticoids suppress CD14 surface expression and release, contributing to their anti-inflammatory effects by reducing monocyte responsiveness to LPS.^[24] Epigenetic regulation, including histone H3 acetylation at the CD14 promoter, also plays a critical role in maintaining accessible chromatin for transcription during monocyte-to-macrophage differentiation.^[25]

Biological Function

Ligand Recognition

CD14 primarily recognizes lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, as its key ligand in innate immune detection. This recognition is greatly facilitated by the formation of a complex with lipopolysaccharide-binding protein (LBP), a serum protein that extracts LPS monomers from bacterial aggregates and presents them to CD14 with enhanced efficiency. The effective binding affinity of this LPS-LBP complex to CD14 is in the low nanomolar range, significantly improving sensitivity compared to LPS binding to CD14 alone, which exhibits micromolar affinity (Kd ≈ 8.7 μM as measured by surface plasmon resonance). LBP acts catalytically in this process, with a 1:1 stoichiometry for LPS:LBP, accelerating the association rate without forming a stable ternary complex detectable under standard conditions.^[26]^[27] The molecular mechanism involves the lipid A portion of LPS inserting into a large hydrophobic pocket located at the N-terminal end of CD14's leucine-rich repeat (LRR) domain, which adopts a curved horseshoe-like structure. This pocket, lined by conserved hydrophobic residues, stabilizes the amphipathic lipid A through non-polar interactions, while positively charged regions nearby may interact with the negatively charged phosphate groups. Soluble CD14 (sCD14), shed from cell surfaces, can bind LPS via this mechanism and subsequently transfer it to membrane-anchored receptors on target cells, amplifying immune responses in CD14-low environments. The crystal structure of human CD14 confirms this pocket's role, measuring approximately 10 Å deep and capable of accommodating a single LPS monomer.^[28]^[4] Beyond LPS, CD14 recognizes other microbial patterns, including peptidoglycan (PGN) and lipoteichoic acid (LTA) from Gram-positive bacteria, with direct binding affinities in the nanomolar range (e.g., Kd ≈ 25 nM for soluble PGN to sCD14). LBP similarly enhances PGN and LTA binding to CD14, promoting their presentation. CD14 also interacts with fungal β-glucans, particulate or soluble forms of which bind via CD14 in cooperation with β2-integrins on phagocytes, facilitating uptake and activation. Non-microbial ligands include exposed phosphatidylserine (PS) on apoptotic cells, where CD14 mediates recognition and phagocytosis by bridging PS to integrins on macrophages.^[29]^[30]^[31]^[32] Binding kinetics are characterized by rapid association, often complete within minutes at physiological temperatures (4–37°C), and are optimal at neutral pH, with reduced efficiency in acidic conditions mimicking endosomal environments. Cooperative enhancement by LBP increases the on-rate by over 100-fold, as demonstrated in binding assays. Specific anti-CD14 monoclonal antibodies, targeting epitopes near the hydrophobic pocket, inhibit LPS, PGN, and LTA binding, confirming CD14's direct involvement. Experimental validation comes from techniques like ELISA for endpoint quantification and surface plasmon resonance (SPR) for real-time kinetic measurements.^[26]^[33]^[27]

Innate Immune Activation

CD14 serves as a critical co-receptor in the innate immune response by facilitating the presentation of lipopolysaccharide (LPS) from Gram-negative bacteria to the Toll-like receptor 4 (TLR4)/MD-2 complex on the cell surface of myeloid cells such as monocytes and macrophages.^[34] This interaction enhances LPS binding affinity, leading to receptor dimerization and recruitment of adaptor proteins that amplify signaling cascades, ultimately promoting the translocation of nuclear factor kappa B (NF-κB) to the nucleus and the transcription of pro-inflammatory genes. In vitro studies demonstrate that CD14-dependent LPS presentation is essential for efficient signal amplification, as cells lacking CD14 exhibit markedly reduced responsiveness to low LPS concentrations.^[35] Upon activation, CD14 initiates robust cellular responses in innate immune cells, particularly the induction of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) in monocytes and macrophages.^[36] These cytokines orchestrate the recruitment and activation of immune cells to combat infection. In endothelial cells, CD14-mediated LPS signaling triggers the expression of adhesion molecules, including E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), facilitating leukocyte adhesion and transmigration across the vascular barrier.^[37] Additionally, CD14 mediates the switch between Fas-mediated cell death and pro-inflammatory signaling by internalizing the Fas receptor, determining the inflammatory output of immune cells.^[38] Soluble CD14 (sCD14), released from activated monocytes, extends LPS responsiveness to CD14-negative cells such as endothelial and epithelial cells by shuttling LPS-LPS-binding protein (LBP) complexes to TLR4/MD-2, thereby enabling inflammatory signaling in non-myeloid tissues.^[39] This mechanism is particularly important in systemic inflammation, where sCD14 amplifies responses in diverse cell types without requiring membrane-bound CD14. The activation process is dose-dependent, with a sensitivity threshold around 10 pg/mL LPS for CD14-expressing cells, below which responses are negligible, as shown in monocyte culture models.^[40] Repeated LPS exposure induces endotoxin tolerance through CD14 downregulation on the cell surface, reducing subsequent inflammatory outputs and preventing excessive cytokine release.^[41] Studies in CD14 knockout mice confirm these roles, revealing hyporesponsiveness to LPS challenge, with diminished cytokine production and protection from endotoxic shock compared to wild-type controls.^[42]

Protein Interactions

Key Binding Partners

CD14 primarily interacts with lipopolysaccharide-binding protein (LBP) to facilitate the capture and transfer of lipopolysaccharide (LPS) from bacterial aggregates to CD14, forming a key complex for innate immune recognition.^[43] This interaction enables LBP to catalyze the binding of LPS monomers to CD14, enhancing the efficiency of LPS presentation to downstream receptors.^[35] Additionally, CD14 associates with Toll-like receptor 4 (TLR4) and MD-2 to transfer LPS into the signaling-competent TLR4/MD-2 complex, where CD14 acts as a co-receptor essential for LPS delivery.^[44] The glycosylphosphatidylinositol (GPI) anchor at the C-terminus of membrane-bound CD14 localizes it to lipid rafts, where it associates with caveolin-1, facilitating compartmentalization of immune signaling components.^[45] Other notable interactors include the integrin CD11b/CD18 (Mac-1), which cooperates with CD14 to enhance non-opsonic phagocytosis of certain pathogens, such as Pseudomonas aeruginosa strains.^[46] Soluble CD14 (sCD14), released from cells or present in plasma, binds LPS and shuttles it to high-density lipoprotein (HDL) particles for lipid transport and detoxification, mitigating excessive inflammation.^[47] Key interaction sites on CD14 include the N-terminal leucine-rich repeats (LRRs), which form a hydrophobic pocket critical for LBP- and LPS-binding, accommodating the acyl chains of LPS.^[4] The C-terminal GPI anchor mediates membrane attachment and raft localization. The CD14-TLR4 interaction reflects transient but specific docking during LPS transfer.^[48] The tripartite LPS-CD14-LBP complex assembles sequentially, with LBP extracting LPS and transferring it to CD14, followed by docking of the CD14-LPS moiety to the TLR4/MD-2 heterodimer to initiate signaling. Structural models derived from cryo-electron microscopy and related techniques reveal the dynamic interface, highlighting how CD14 bridges LPS delivery to the TLR4/MD-2 pocket for dimerization and activation.^[35]

Downstream Signaling Pathways

Upon recognition of lipopolysaccharide (LPS) by the CD14-TLR4-MD-2 complex at the plasma membrane, the canonical MyD88-dependent pathway is initiated, wherein MyD88 is recruited to the Toll/interleukin-1 receptor (TIR) domain of TLR4, forming a complex that activates interleukin-1 receptor-associated kinases (IRAKs).^[49] IRAK4 phosphorylates IRAK1, leading to its ubiquitination and association with tumor necrosis factor receptor-associated factor 6 (TRAF6), which undergoes K63-linked ubiquitination to activate the transforming growth factor-β-activated kinase 1 (TAK1) complex.^[50] TAK1 then phosphorylates the IκB kinase (IKK) complex, resulting in the degradation of IκB and nuclear translocation of NF-κB, which drives transcription of pro-inflammatory genes such as those encoding TNF-α and IL-6.^[49] Concurrently, TAK1 activates mitogen-activated protein kinases (MAPKs), including p38, JNK, and ERK, further amplifying inflammatory responses through AP-1 transcription factor activation.^[50] In parallel, the non-canonical TRIF-dependent pathway is engaged following CD14-mediated endocytosis of the TLR4 complex into early endosomes, where TRIF-related adaptor molecule (TRAM) bridges TLR4 to TIR-domain-containing adapter-inducing interferon-β (TRIF).^[51] TRIF recruits TRAF6 and receptor-interacting protein kinase 1 (RIPK1) to activate TAK1 and subsequently TBK1/IKKε, which phosphorylate interferon regulatory factor 3 (IRF3).^[51] Phosphorylated IRF3 dimerizes and translocates to the nucleus, inducing type I interferon (IFN-α/β) production and late-phase NF-κB activation for sustained cytokine expression.^[52] This endosomal signaling is distinct from the plasma membrane-localized MyD88 pathway, allowing compartmentalized control of antiviral and inflammatory outputs.^[51] Signaling through these pathways is modulated by negative regulators to prevent excessive inflammation; for instance, phosphatidylinositol 3-kinase (PI3K)/Akt activation downstream of CD14-TLR4 inhibits NF-κB by promoting IκB stability and FOXO3a-mediated transcription of anti-inflammatory genes.^[53] Single-cell phosphoproteomics studies reveal dynamic phosphorylation kinetics, with peak activation of key nodes like p65 NF-κB occurring within 15-60 minutes post-LPS stimulation, correlating with TNF-α secretion peaking at 2-4 hours in human macrophages.^[54]^[55] Negative feedback is further enforced by SIGIRR, which competes for IRAK-TRAF6 interactions to attenuate MyD88 signaling, and SOCS1, which ubiquitinates TRAF6 and inhibits JAK-STAT crosstalk for dampened cytokine production.^[56]^[57] Species-specific variations in CD14-mediated signaling influence outcomes; in mice, CD14 is more critical for endosomal TRIF pathway activation compared to humans, where plasma membrane signaling predominates in dendritic cells.^[49] CD14-deficient mouse models exhibit markedly reduced cytokine responses to LPS, including lower TNF-α and IL-6 levels, conferring protection against endotoxin-induced shock and cytokine storms in sepsis models.^[42]^[58]

Clinical and Pathological Roles

Involvement in Diseases

CD14 plays a critical role in the pathogenesis of sepsis and endotoxemia, where dysregulation amplifies inflammatory responses to bacterial lipopolysaccharides (LPS). Elevated levels of soluble CD14 (sCD14) in plasma are strongly correlated with disease severity. Genetic polymorphisms in the CD14 gene, such as the C-159T variant, further exacerbate risk, conferring approximately a 2-fold increased susceptibility to Gram-negative infections like brucellosis through enhanced monocyte activation and cytokine production.^[13] In chronic inflammatory conditions, CD14 contributes to disease progression by facilitating monocyte differentiation into pro-inflammatory foam cells. In atherosclerosis, CD14 expression on macrophages promotes oxidized LDL uptake and foam cell formation, which destabilizes plaques by driving matrix metalloproteinase release and necrotic core expansion.^[59] Similarly, in inflammatory bowel disease (IBD), CD14 is upregulated on colonic macrophages, enhancing LPS-mediated inflammation and disrupting epithelial barrier integrity in affected tissues.^[60] CD14 also links to neurodegenerative pathology in Alzheimer's disease, where it mediates microglial activation in response to amyloid-β fibrils, exacerbating neuroinflammation and plaque-associated neuronal damage.^[61] Beyond these, CD14 variants influence respiratory disorders, including asthma, where polymorphisms like C-159T modulate airway hyperresponsiveness and allergen-induced inflammation, altering endotoxin tolerance and IgE responses.^[62] In COVID-19, studies from 2020 to 2023 highlight sCD14 as a prognostic marker for severe outcomes, with elevated levels (e.g., >3 μg/mL) associated with worse prognosis including cytokine storm and progression to acute respiratory distress syndrome (ARDS) in critically ill patients.^[63] Experimental evidence from large-scale human cohort studies, including those with over 500 sepsis patients, underscores CD14's pathological impact, showing that high sCD14 correlates with multi-organ failure and 28-day mortality.^[64] In animal models of polymicrobial sepsis, CD14 blockade using monoclonal antibodies significantly reduces mortality by 30-50% and attenuates thrombo-inflammation, organ dysfunction, and cytokine release, supporting its therapeutic targeting.^[65]

Diagnostic and Therapeutic Potential

Soluble CD14 subtype (sCD14-ST), also known as presepsin, serves as a biomarker for sepsis diagnosis, with plasma levels measurable via enzyme-linked immunosorbent assay (ELISA). A systematic review and meta-analysis of 30 studies reported pooled sensitivity of 78% and specificity of 83% for presepsin in distinguishing sepsis from non-infectious systemic inflammatory response syndrome.^[66] Elevated presepsin levels are particularly indicative of bacterial infections, aiding differentiation from viral etiologies in emergency settings, where bacterial cases show significantly higher concentrations compared to viral infections.^[67] Therapeutically, anti-CD14 monoclonal antibodies like IC14 have been investigated to mitigate excessive immune activation in inflammatory conditions. In a phase I trial involving endotoxemia models, IC14 significantly inhibited lipopolysaccharide (LPS)-induced proinflammatory cytokine release, including tumor necrosis factor-alpha and interleukin-6, while attenuating clinical symptoms.^[68] A phase II randomized, double-blind, placebo-controlled trial in hospitalized patients with acute respiratory distress syndrome (ARDS) due to severe COVID-19 demonstrated that IC14 reduced systemic inflammation markers, with numerical improvements in 28-day mortality among those with high baseline presepsin levels.^[69] Extracorporeal therapies targeting endotoxin, which interacts with CD14 to drive endotoxemia, have shown promise in sepsis management by adsorbing circulating LPS, thereby indirectly neutralizing CD14-mediated responses.^[70] CD14 exhibits prognostic value in various diseases, particularly through soluble forms and monocyte expression levels. In chronic lymphocytic leukemia (CLL), elevated serum sCD14 correlates with advanced disease stage and poorer survival, serving as an independent prognostic marker beyond traditional factors like absolute monocyte count.^[71] Similarly, increased CD14+ monocyte subsets in acute leukemia are associated with disease progression and worse outcomes.^[72] In neurodegeneration, higher plasma sCD14 levels predict incident dementia; a meta-analysis across two population-based cohorts found that each standard deviation increase in sCD14 was linked to a 12% higher risk (odds ratio 1.12, 95% CI 1.01-1.25).^[73] Experimental models further support this, showing that CD14 deficiency delays Alzheimer's disease pathology by influencing microglial responses.^[74]

References

[1]
Role of CD14 in human disease - PMC - NIH
The cell surface antigen CD14 is primarily understood to act as a co-receptor for toll-like receptors (TLRs) to activate innate immunity responses.
[2]
http://www.ncbi.nlm.nih.gov/gene/929
[3]
The impact of glycosylation on the structure, function, and ... - NIH
CD14 is an innate immune receptor that senses pathogen-associated molecular patterns, such as lipopolysaccharide, to activate the innate immune response.
[4]
Gene - CD14
### CD14 Gene Summary
[5]
CD14 CD14 molecule [Homo sapiens (human)] - Gene - NCBI
### Summary of CD14 Gene (https://www.ncbi.nlm.nih.gov/gene/929)
[6]
Sp1 is a critical factor for the monocytic specific expression of human ...
Apr 15, 1994 · The Sp1 transcription factor bound to three different regions in the CD14 promoter. Mutation of the major Sp1 binding site (-110 bp) ...Missing: PU. | Show results with:PU.
[7]
Sp1 is a critical factor for the monocytic specific expression of human ...
CD14 Sp1 site oligonucleotides bound preferentially to a 105-kDa Sp1 species, which is present in higher relative levels in monocytic than non-monocytic cells, ...
[8]
12475 - Gene ResultCd14 CD14 antigen [ (house mouse)] - NCBI
Sep 30, 2025 · This gene encodes a protein that plays an important role in the innate immune response and is expressed in monocyte/macrophage cells.Missing: chromosome | Show results with:chromosome
[9]
Coevolution of the Toll-Like Receptor 4 Complex with Calgranulins ...
Feb 21, 2018 · Our work demonstrates that calgranulin activation of TLR4 evolved at least ~320 million years ago and has been conserved in the amniote innate immune system.Figure 1 · Calgranulins And Lps... · Plasmids And Recombinant...
[10]
In silico analyses of CD14 molecule reveal significant evolutionary ...
Jul 12, 2019 · In silico analyses of CD14 molecule reveal significant evolutionary diversity, potentially associated with speciation and variable immune ...
[11]
Association of a Promoter Polymorphism of the CD14 Gene and Atopy
Apr 14, 2000 · We conclude that the − 159 C-to-T promoter polymorphism in the CD14 gene may result in expression of a more severe allergic phenotype. Atopic ...Missing: 159T | Show results with:159T
[12]
Relationship between CD14-159C/T gene polymorphism and acute ...
One of the most extensively studied SNPs, the -159C/T (rs2569190), includes a substitution of C → T resulting in elevated transcriptional activity and ...
[13]
p08571 · cd14_human - UniProt
Computationally mapped potential isoform sequences ; D6RFL4, D6RFL4_HUMAN, CD14, 213 ; D6RD81, D6RD81_HUMAN, CD14, 55 ...
[14]
Recombinant Human CD14 Protein 383-CD-050 - R&D Systems
Rating 5.0 (3) · $45 deliveryThe human CD14 cDNA encodes a 375 amino acid (aa) residue precursor protein with a 19 aa signal peptide and a C-terminal hydrophobic region characteristic ...Missing: length | Show results with:length
[15]
Structural relationship between the soluble and membrane-bound ...
The carboxy-terminal amino acid sequence of the soluble form of the 53,000 mol. wt monocyte surface antigen, CD14, was determined by carboxypeptidase Y ...
[16]
The crystal structure of human soluble CD14 reveals a bent solenoid ...
CD14 is best known as a pattern recognition receptor of the innate immune system that plays a prominent role in sensitizing cells to the presence of Gram- ...
[17]
The Differential Impact of Disulfide Bonds and N-Linked ...
Two of the four predicted glycosylation sites, asparagines 132 and 263, are actually involved in N-linked glycosylation, resulting in heterogeneity in CD14 ...
[18]
Human B cells express membrane-bound and soluble forms of the ...
The molecule expressed in the normal B and B-type chronic lymphocytic leukemia cells was identical in size to the 52,000 mol. wt monocyte-isolated CD14 ...<|control11|><|separator|>
[19]
The CD14 monocyte differentiation antigen maps to a ... - PubMed
Jan 29, 1988 · CD14 is a myelomonocytic differentiation antigen expressed by monocytes, macrophages, and activated granulocytes and is detectable with the monoclonal ...Missing: discovery 1980s
[20]
and CD14+ human normal myeloid precursors - Nature
Jun 10, 2005 · We purified CD14− and CD14+ myeloid precursors generated by 'in vitro' culture of human CD34+ hematopoietic progenitors.Missing: monopoiesis | Show results with:monopoiesis
[21]
https://www.nature.com/articles/4401679
[22]
Expression and release of the monocyte lipopolysaccharide ...
Feb 1, 1997 · Expression and release of the monocyte lipopolysaccharide receptor antigen CD14 are suppressed by glucocorticoids in vivo and in vitro.
[23]
Genome-wide promoter analysis of histone modifications in human ...
Nov 18, 2010 · For example, CD14 and CD4 genes had double H3K4me3/AcH3 mark on their promoters in monocytes, where they are expressed at high levels, but in ...
[24]
binding protein accelerates the binding of LPS to CD14. | Journal of ...
Jan 1, 1994 · Recombinant LBP (rLBP) does not form detectable ternary complexes with rsCD14 and LPS, but it does accelerate the binding of LPS to rsCD14.
[25]
https://bmcgenomics.biomedcentral.com/articles/10.1186/1471-2164-11-642
[26]
Binding of bacterial peptidoglycan to CD14 - PubMed - NIH
Apr 10, 1998 · ... (KD = 25 nM versus 41 nM). LPS-binding protein (LBP) increased the binding of sCD14 to sPGN by adding another lower affinity KD and another ...
[27]
Involvement of CD14 and β2-Integrins in Activating Cells with ...
The addition of recombinant LPS binding protein (LBP) and/or soluble CD14 (sCD14) enhanced the production of TNF from monocytes stimulated with soluble LPS, ...
[28]
CD14-dependent clearance of apoptotic cells by human macrophages
Apr 16, 2003 · CD14 has the proven ability to bind phospholipids and may function as an alternative receptor for the externalised PS of apoptotic cells.
[29]
Analysis of lipopolysaccharide binding by CD14. - ScienceDirect.com
The cell surface protein CD14 binds bacterial lipopolysaccharide (LPS) in the presence of the serum protein, LPS-binding protein (LBP).
[30]
Essential roles of CD14 and lipopolysaccharide‐binding protein for ...
Dec 20, 2001 · The results indicate that CD14 and LBP are essential and sufficient for the activation of the TLR2- or TLR4-expressing cells by LPS. Discussion.Missing: affinity | Show results with:affinity
[31]
Critical Role of CD14 for Production of Proinflammatory Cytokines ...
Our results indicate that the CD14 pathway of activation plays a critical role in the production of both pro-inflammatory cytokines and cytokine inhibitors.
[32]
Glutathione peroxidase-1 modulates lipopolysaccharide-induced ...
Mar 10, 2010 · Glutathione peroxidase-1 modulates lipopolysaccharide-induced adhesion molecule expression in endothelial cells by altering CD14 expression.
[33]
Soluble CD14 | Arteriosclerosis, Thrombosis, and Vascular Biology
Nov 15, 2012 · CD14 also exists as a soluble form (sCD14). In addition to secretion from liver, sCD14 may be derived by enzymatic cleavage of GPI-anchored cell ...
[34]
Role of the lipopolysaccharide (LPS)-binding protein/CD14 pathway ...
We suggest that low levels of LPS (5 to 100 pg/mL) present during sepsis induce TF expression in monocytes via the LBP/CD14-dependent pathway.
[35]
Differential Regulation of Membrane CD14 Expression and ... - NIH
A potential mechanism whereby endotoxin-tolerance develops is the downregulation of LPS receptors such as mCD14 on macrophages (16, 20). The objectives of this ...
[36]
CD14-deficient mice are protected against lipopolysaccharide ...
LPS-treated CD14-D mice maintained normal cardiac function. Conclusions: These results suggest that CD14 is important in mediating the proinflammatory response ...
[37]
CD14, a Receptor for Complexes of Lipopolysaccharide (LPS) and ...
CD14, a differentiation antigen of monocytes, was found to bind complexes of LPS and LBP, and blockade of CD14 with monoclonal antibodies prevented synthesis ...<|control11|><|separator|>
[38]
Lipopolysaccharide Interaction with Cell Surface Toll-like Receptor 4 ...
Sep 29, 2003 · CD14 greatly enhances the formation of LPS–TLR4-MD-2 complexes, but is not coprecipitated with LPS–TLR4-MD-2 complexes, suggesting a role for ...
[39]
Lipid rafts in immune signalling: current progress and future ...
May 7, 2016 · 55 broadly showed that caveolin-1 not only regulates TLR4 signalling but also regulates CD14, CD36 and MyD88 protein expression in macrophages ...MicroRNAs as modulators of... · Lipid rafts involved in... · Lipid rafts alter cytokine...
[40]
Distinct Contributions of CD18 Integrins for Binding and Phagocytic ...
... (CD18/CD11b) facilitates nonopsonic phagocytosis of some P. aeruginosa strains; uptake of other strains was dependent on interactions with CD14 (a ...
[41]
Soluble CD14 acts as a shuttle in the neutralization of ...
May 1, 1995 · Several observations suggest that sCD14 accelerates this reaction by serving as a shuttle for LPS: addition of LBP and sCD14 to LPS micelles ...Missing: albumin transport
[42]
Co-operation of TLR4 and raft proteins in LPS-induced pro ... - NIH
Notably, FRET analysis indicated that tetraspanin CD81, integrin β2 (CD11/CD18) and Fcγ receptors gather in the vicinity of CD14 and TLR4 in LPS-stimulated ...
[43]
TLR4 and CD14 trafficking and its influence on LPS-induced pro ...
The LPS-induced internalization of TLR4 and hence also the activation of the TRIF-dependent pathway is governed by a GPI-anchored protein, CD14. The endocytosis ...
[44]
Multifaceted role of CD14 in innate immunity and tissue homeostasis
CD14 expression has been observed in macrophages and in other myelomonocyte lineages, including monocytes, neutrophils, and dendritic cells [5], [6].
[45]
An examination of the LPS-TLR4 immune response through the ...
Mar 18, 2025 · Upon LPS binding, CD14 delivers LPS to the TLR4-MD-2 complex through direct TLR4 interaction, subsequently promoting TLR4-mediated intracellular ...
[46]
Acetylation of TIR domains in the TLR4-Mal-MyD88 complex ...
Sep 18, 2024 · In the MyD88-independent pathway, the TLR4-mediated signaling pathway requires two adaptor molecules, TRAM and TRIF. TRAM is thought to bridge ...
[47]
TLR4/CD14-mediated PI3K activation is an essential component of ...
We show that VSV induces TLR4 (and CD14)-dependent Akt phosphorylation. We observed hypersusceptibility to viral infections after pharmacological inactivation ...Missing: SOCS1 | Show results with:SOCS1
[48]
Phosphoproteome Profiling: Macrophage Response to TLR Ligands
We investigated the differences in the phosphoprotein signaling cascades triggered by TLR2, TLR4, and TLR7 ligands using a single responding cell population.
[49]
Higher LPS-stimulated TNF-α mRNA levels in peripheral blood ...
After LPS stimulation, the relative amounts of TNF increased early, with the maximum level observed at 2 and 4 hours, and then decreased until 24 hours (Table 5 ...Whole Blood Cell Culture And... · Tnf Protein Dosage · Peripheral Blood Cells And...
[50]
SIGIRR participates in negative regulation of LPS response ... - NIH
Dec 3, 2015 · 5a), indicating that SIGIRR expressed in T24 and 5637 cells functions as a negative regulator of TLR-4 signaling. ... Previous mechanistic studies ...
[51]
SOCS1, a Negative Regulator of Cytokine Signals and TLR ...
SOCS1, a member of SOCS family, is strongly induced upon TLR stimulation. Cells lacking SOCS1 are hyperresponsive to TLR stimulation.
[52]
Role of CD14 in host protection against infections and in metabolism ...
Jul 23, 2013 · Based on these observations it emerges that CD14 plays a crucial role in regulating cellular responses to LPS by: (i) controlling LPS ...Abstract · Introduction · CD14 and the LPS Receptor... · CD14 Signaling Capacities<|separator|>
[53]
Markers for sepsis diagnosis in the forensic setting: state of the art
They observed increased (>10 µg/mL) values in most septic cases and reference (<10 µg/mL) levels in most control cases, thereby confirming a high diagnostic ...
[54]
Inflammation‐induced foam cell formation in chronic inflammatory ...
Mar 10, 2015 · Two models describe early events initiating atherosclerotic plaque formation, whereby foam cells form in response to hyperlipidaemia or inflammation-associated ...Role Of Monocytes In The... · Monocyte Activation In... · Tlr Activation In...
[55]
Expression of Toll-like Receptor 2 (TLR2), TLR4, and CD14 in ... - NIH
Significant upregulation of CD14 expression on macrophages was identified in areas affected by IBD ... colonic macrophages in inflammatory bowel disease. Eur J ...
[56]
CD14 and Toll-Like Receptors 2 and 4 Are Required for Fibrillar Aβ ...
Sep 23, 2009 · We report that CD14, TLR4, and TLR2 are necessary for binding fAβ at the cell surface, and are required for phenotypic activation of microglia and induction of ...
[57]
CD14, Endotoxin, and Asthma Risk: Actions and Interactions - PMC
From the point of view of asthma and allergies, interest in this gene was twofold: first, CD14 is located in chromosome 5q31, a region that several genome-wide ...Missing: exons structure
[58]
Plasma Soluble CD14 Subtype Levels Are Associated With Clinical ...
Dec 9, 2021 · An elevated circulating level of sCD14-ST is specific and sensitive for the diagnosis of bacterial sepsis, predicts mortality in sepsis and ...
[59]
CD14 inhibition improves survival and attenuates thrombo ... - NIH
Objectives: We investigated the effect of CD14 blockade on sepsis-induced coagulopathy, inflammation, organ dysfunction, and mortality. Methods:.
[60]
Accuracy of Presepsin in Sepsis Diagnosis: A Systematic Review ...
The pooled sensitivity of presepsin for sepsis was 0.78 (0.76–0.80), pooled specificity was 0.83 (0.80–0.85), pooled positive likelihood ratio was 4.63 (3.27– ...
[61]
Presepsin Levels in Emergency Patients with Bacterial and Viral ...
Blood presepsin levels are used as a tool to identify patients who may suffer from sepsis caused by bacterial infection, necessitating immediate antibiotic ...
[62]
IC14, an anti-CD14 antibody, inhibits endotoxin-mediated ... - PubMed
Mar 1, 2001 · IC14 attenuated LPS-induced clinical symptoms and strongly inhibited LPS-induced proinflammatory cytokine release, while only delaying the ...
[63]
Phase 2, randomized, double-blind, placebo-controlled multi-center ...
Jun 17, 2023 · In early phase clinical trials in bacterial sepsis and ARDS, IC14 reduced systemic inflammation (e.g. circulating IL-6, TNF-α, MIP-1beta ...
[64]
(PDF) Rationale of Extracorporeal Removal of Endotoxin in Sepsis
Aug 9, 2025 · CD14 and Toll-like receptor-4, are particularly sensitive to the presence of LPS. They respond by producing inflammatory mediators which enhance ...
[65]
Evaluation of Prognostic Impact of Soluble CD14 in B-Chronic ... - NIH
Soluble CD14 is a novel monocyte-derived survival factor for chronic lymphocytic leukemia cells, which is induced by CLL cells in vitro and present at ...
[66]
Expansion of CD14+CD16+ monocytes is related to acute leukemia
Conclusions: The proportion of CD14+CD16+ monocytes (especially the intermediate subpopulation) is related to the progression of acute leukemia, and the ...
[67]
Association of CD14 with incident dementia and markers of brain ...
Meta-analysis across the 2 cohorts showed that each SD unit increase in sCD14 was associated with a 12% increase in the risk of incident dementia (95% ...
[68]
Deletion of CD14 Attenuates Alzheimer's Disease Pathology by ...
Nov 17, 2010 · These data suggest critical roles for TLRs and their coreceptors in disease progression and development of microglial phenotypic heterogeneity.