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Phagocyte

Phagocytes are specialized white blood cells that perform phagocytosis, a fundamental cellular process involving the recognition, engulfment, and destruction of large particles greater than 0.5 μm in diameter, such as microorganisms, foreign substances, and apoptotic cells.^[1] These cells form a critical component of the innate immune system, rapidly clearing pathogens and debris to prevent infection and maintain tissue homeostasis, while also contributing to adaptive immunity through antigen presentation.^[2] Discovered by Élie Metchnikoff in the late 19th century through observations of starfish larvae, phagocytosis was recognized as a key immunobiological mechanism, earning Metchnikoff the Nobel Prize in Physiology or Medicine in 1908.^[2] Phagocytes are broadly classified into professional and non-professional types based on their efficiency in particle ingestion. Professional phagocytes, which exhibit high phagocytic activity, include neutrophils, monocytes, macrophages, dendritic cells, eosinophils, and osteoclasts; these cells express a variety of receptors, such as Fcγ receptors and complement receptors, to recognize opsonized targets and initiate engulfment via actin cytoskeleton remodeling.^[1] Neutrophils, the most abundant circulating leukocytes (approximately 4.2 × 10⁹/L in humans), provide rapid responses to bacterial infections through phagocytosis, release of reactive oxygen species, and formation of neutrophil extracellular traps (NETs), though they have a short lifespan of approximately 5 days in circulation.^[3]^[4] Macrophages, often tissue-resident and long-lived (e.g., up to 4.2 years for microglia in the brain), serve as sentinels for chronic surveillance, clearing apoptotic cells and orchestrating inflammation resolution.^[3] Monocytes, their circulating precursors, differentiate into macrophages or dendritic cells upon entering tissues, supporting immune surveillance with a circulation half-life of around 20 hours.^[3] Dendritic cells, bone marrow-derived and short-lived, with a circulating lifespan of approximately 1–2 days, excel in antigen presentation to T cells, bridging innate and adaptive responses.^[3]^[5] In addition to pathogen elimination, phagocytes regulate immune tolerance by efficiently removing billions of apoptotic cells daily without triggering inflammation, a process essential for preventing autoimmunity and promoting tissue repair.^[2] Defects in phagocyte function, such as those seen in chronic granulomatous disease, compromise host defense and lead to recurrent infections, underscoring their indispensable role in immunity.^[6]

Fundamentals

Definition and Characteristics

Phagocytes are specialized immune cells that engulf and destroy pathogens, cellular debris, and apoptotic cells through the process of phagocytosis, a fundamental mechanism in innate immunity and tissue homeostasis.^[7] Phagocytosis represents a specialized form of endocytosis dedicated to internalizing large particles exceeding 0.5 μm in diameter, distinguishing it from other endocytic pathways that handle smaller entities.^[7] This capability enables phagocytes to clear microbial invaders and maintain cellular integrity by removing damaged or dying cells.^[8] Structurally, phagocytes are equipped with key organelles and components essential for their function, including phagosomes—membrane-derived vesicles that encapsulate engulfed material—and lysosomes that fuse with phagosomes to form phagolysosomes, creating an acidic environment (pH as low as 4.5) for enzymatic degradation.^[8] The cytoskeleton plays a critical role, with actin polymerization driven by complexes like Arp2/3 and regulated by GTPases (such as Rac, Cdc42, and RhoA) facilitating pseudopod extension and particle internalization.^[8] Phagocytes are broadly classified into professional and non-professional types based on phagocytic efficiency: professional phagocytes, including macrophages, neutrophils, monocytes, dendritic cells, and eosinophils, execute phagocytosis as a primary duty with high proficiency, whereas non-professional phagocytes, such as fibroblasts, epithelial cells, and endothelial cells, perform it less efficiently, primarily for apoptotic cell clearance.^[7] Morphologically, phagocytes exhibit features adapted to their roles, with macrophages typically being large cells (20–30 μm in diameter) featuring irregular or kidney-shaped nuclei and abundant, vacuole-rich cytoplasm that supports extensive phagocytic activity.^[9] In contrast, neutrophils display multilobulated nuclei and granular cytoplasm containing antimicrobial enzymes and granules, enabling rapid responses to infection despite their smaller size (around 10–12 μm).^[9] These traits underscore the diversity among phagocyte subtypes while unifying their core engulfment and destructive capabilities.^[7]

Biological Roles and Importance

Phagocytes constitute the primary effectors of innate immunity, acting as the first line of defense against invading pathogens by rapidly recognizing, engulfing, and destroying microbial threats through phagocytosis. This process limits infection dissemination and initiates inflammatory responses to recruit additional immune cells, ensuring host protection in the absence of prior antigen exposure.^[10]^[11] Beyond pathogen control, phagocytes play crucial roles in tissue homeostasis by clearing apoptotic cells and debris, a process known as efferocytosis that prevents the release of intracellular contents and subsequent autoimmunity. In humans, phagocytes process approximately 10 to 100 billion apoptotic cells daily, primarily neutrophils from circulation, maintaining immune tolerance and avoiding chronic inflammation from uncleared debris.^[12]^[13] Additionally, phagocytes contribute to tissue remodeling during embryonic development and wound healing, where they prune unnecessary structures and orchestrate extracellular matrix reorganization to support regeneration and fibrosis resolution.^[14]^[15] In healthy states, they sustain sterile environments in barrier tissues such as the lungs and gut; alveolar macrophages in the lungs surveil for airborne pathogens while minimizing inflammation, and intestinal macrophages balance microbiota tolerance with rapid clearance of invasive microbes to preserve mucosal integrity.^[16]^[17] Phagocytes also bridge innate and adaptive immunity by processing engulfed antigens and presenting them via major histocompatibility complex molecules to T cells, thereby priming specific humoral and cellular responses.^[18] In pathology, phagocyte dysregulation drives chronic inflammation, as seen in atherosclerosis where monocyte-derived macrophages accumulate oxidized lipids in arterial walls, perpetuating plaque formation and vascular damage.^[19] In cancer, tumor-associated macrophages contribute to immune surveillance by phagocytosing malignant cells expressing "eat me" signals, although their polarization often shifts to pro-tumorigenic states that suppress anti-tumor immunity.^[20] Recent post-2020 studies highlight phagocytic roles in neuroinflammation, particularly microglia in Alzheimer's disease, where impaired efferocytosis of amyloid-beta aggregates and synaptic debris exacerbates plaque buildup and neuronal loss due to genetic risk factors like TREM2 variants; as of 2025, research has further shown that lipid droplet accumulation in microglia impairs phagocytosis, and their clearance enhances Aβ uptake.^[21]^[22]^[23]

Historical Development

Early Observations

The earliest observations of white blood cell mobility in tissues were made by German pathologist Julius Cohnheim in 1867, who demonstrated through microscopic studies of inflamed frog mesentery that leukocytes could migrate across intact capillary walls via amoeboid movement, a process he termed diapedesis.^[24] This finding established the foundational concept of leukocyte emigration from blood vessels to sites of injury or infection, laying the groundwork for understanding cellular involvement in inflammation.^[25] A pivotal advancement came in 1882 when Russian zoologist Élie Metchnikoff, while studying embryonic development in starfish larvae at the Messina Marine Biological Station, observed mobile mesodermal cells actively engulfing foreign particles.^[26] In a seminal experiment, Metchnikoff inserted rose thorns into the transparent larvae and noted that phagocytic cells rapidly surrounded and internalized the intruding material, interpreting this as a defensive cellular response against nonself entities.^[27] This discovery introduced the term "phagocytosis" to describe the process, shifting focus from passive humoral defenses to active cellular immunity.^[28] Metchnikoff extended these insights through experiments on bacterial infections, particularly using anthrax bacilli (Bacillus anthracis) in guinea pigs during the 1880s.^[26] He injected the bacilli subcutaneously and observed that mobile leukocytes at the site of injection engulfed and destroyed the pathogens in the exuded fluid, with similar phagocytic activity noted in the peritoneal cavity.^[26] These studies, conducted at the Pasteur Institute, highlighted the protective role of phagocytes in resisting anthrax, a model for understanding cellular defenses against microbial threats.^[27] These early findings sparked intense debate within the scientific community regarding the primacy of cellular versus humoral immunity. Metchnikoff championed phagocytosis as the central defensive process, but this view clashed with the toxin-based humoral theories advocated by bacteriologists like Robert Koch, who emphasized soluble factors and antitoxins as the main agents of protection against diseases such as anthrax.^[27] The controversy underscored initial misconceptions that cellular activity was merely secondary to chemical defenses, delaying widespread acceptance of phagocytes' independent role until later experimental validations.

Key Milestones and Researchers

In 1908, Élie Metchnikoff and Paul Ehrlich were awarded the Nobel Prize in Physiology or Medicine for their foundational work on immunity, with Metchnikoff's contributions emphasizing the role of phagocytes in cellular immunity through his earlier observations of phagocytosis in starfish larvae and mammals. Metchnikoff, often regarded as the father of cellular immunology, demonstrated in the late 19th and early 20th centuries that phagocytes actively engulf and destroy pathogens, laying the groundwork for understanding innate immunity. The mid-20th century brought advances in visualizing phagocyte function through electron microscopy, notably in the 1950s when studies revealed the fusion of phagosomes with lysosomes, elucidating the intracellular digestion process essential for pathogen elimination. This technological leap shifted research from light microscopy to ultrastructural details, enabling precise mapping of phagocytic compartments. By the 1970s, the identification of reactive oxygen species (ROS) as key antimicrobial agents in phagocytes marked a pivotal biochemical milestone, with Bernard Babior's work at the Scripps Clinic demonstrating that activated neutrophils generate superoxide via the NADPH oxidase complex during the respiratory burst. This discovery explained the molecular basis of oxidative killing and linked defects in ROS production to chronic granulomatous disease. The transition to molecular biology in the late 20th and early 21st centuries accelerated with genetic tools; for instance, the 2010s saw CRISPR-Cas9 applications in dissecting phagocytic receptors, including studies on Fcγ receptors that mediate antibody-dependent phagocytosis in macrophages. Ralph Steinman, who co-discovered dendritic cells in the 1970s and received the 2011 Nobel Prize in Physiology or Medicine for this work, highlighted their unique phagocytic and antigen-presenting roles, bridging innate and adaptive immunity. Recent advances, such as single-cell RNA sequencing since the mid-2010s, have unveiled the heterogeneity of phagocyte populations, revealing diverse transcriptional states in macrophages across tissues and disease contexts.^[29] This evolution from morphological observations to genomic and functional profiling underscores the field's progression toward precision immunology.

Phagocytosis Mechanism

Recognition and Engulfment

Phagocytes recognize and bind to target particles, such as pathogens or apoptotic cells, through specialized surface receptors that initiate the engulfment process. This recognition phase is crucial for distinguishing harmful entities from host tissues and ensuring selective internalization. Recognition can occur via opsonin-dependent or non-opsonic mechanisms, each involving distinct receptor-ligand interactions.^[1] In opsonin-dependent recognition, soluble host proteins known as opsonins coat the target, enhancing its visibility to phagocytes. Antibodies, particularly immunoglobulin G (IgG), bind to microbial antigens and are detected by Fcγ receptors (FcγR) on the phagocyte surface, triggering signaling cascades that promote attachment and uptake. Complement proteins, such as C3b, opsonize targets following activation of the complement system and are recognized primarily by complement receptor 1 (CR1) and complement receptor 3 (CR3), facilitating phagocytosis of bacteria and immune complexes. These opsonic pathways amplify the efficiency of recognition, particularly for immune complexes and opsonized pathogens.^[2]^[1]^[2] Non-opsonic recognition allows direct binding without opsonin intermediaries, relying on pattern recognition receptors that detect specific molecular motifs. For instance, the mannose receptor on macrophages binds to mannose-containing glycans on fungal and bacterial surfaces, enabling uptake of pathogens like Mycobacterium species. In the clearance of apoptotic cells, exposed phosphatidylserine on the outer membrane leaflet is recognized by receptors such as stabilin-2 or TIM-4, promoting non-inflammatory engulfment to maintain tissue homeostasis. These mechanisms ensure phagocytosis of unopsonized targets, including certain microbes and dying cells.^[1]^[30]^[30] Upon recognition, engulfment proceeds through dynamic cytoskeletal rearrangements that internalize the target into a membrane-bound phagosome. The process begins with receptor clustering at the contact site, leading to localized actin polymerization that drives pseudopod extension around the particle, forming a phagocytic cup. Actin filaments, nucleated by the Arp2/3 complex, provide the protrusive force necessary for membrane protrusion and target enclosure. The phagocytic cup seals at the base, pinching off to generate an intracellular phagosome containing the engulfed material.^[31]^[32] Engulfment mechanisms vary based on target size and receptor type, with two primary modes observed: zippering and sinking. Zippering phagocytosis, typically mediated by Fcγ receptors, involves sequential engagement of receptors along the target surface, resulting in tight pseudopod wrapping and efficient uptake of small to medium particles like opsonized bacteria. In contrast, sinking phagocytosis, often driven by complement receptors like CR3, submerges the target into the cell interior without extensive pseudopod formation, suitable for larger or deformable particles such as erythrocytes. These modes ensure adaptability to diverse targets while maintaining phagosome integrity.^[33]^[33] The engulfment process is energy-intensive and ATP-dependent, relying on ATP hydrolysis to fuel actin dynamics and membrane remodeling. Rho family GTPases, including Rac1 and Cdc42, play pivotal roles in orchestrating cytoskeletal changes; Rac1 promotes lamellipodia-like pseudopod extension, while Cdc42 drives filopodia formation and initial actin nucleation at the phagocytic site. These GTPases activate downstream effectors like WAVE and N-WASP to stimulate Arp2/3-mediated branching of actin filaments, ensuring coordinated pseudopod progression and phagosome closure.^[34]^[35]^[35] Efficiency of recognition and engulfment varies among phagocyte types, influenced by receptor expression and cytoskeletal capacity. Neutrophils exhibit high phagocytic rates for small pathogens, capable of engulfing up to 50 bacteria per cell, whereas macrophages handle larger particles more effectively due to their expansive pseudopods. Dendritic cells, while proficient in antigen sampling, show moderated engulfment to preserve target integrity for presentation. Monocytes display lower baseline efficiency, which increases upon differentiation into macrophages.^[1]^[36]

Intracellular Killing and Digestion

Following the closure of the phagosome during engulfment, phagocytes initiate a series of maturation events that transform the nascent phagosome into a microbicidal compartment capable of destroying engulfed pathogens. The phagosome progressively fuses with early endosomes, late endosomes, and ultimately lysosomes, culminating in the formation of the phagolysosome.^[37] This maturation process involves the recruitment of Rab GTPases and SNARE proteins, which facilitate organelle fusion and the delivery of lysosomal contents.^[38] A critical aspect of phagolysosome function is acidification, primarily driven by the vacuolar-type H+-ATPase (V-ATPase) proton pump, which lowers the intraluminal pH from neutral to approximately 4.5–5.5.^[37] This acidic environment activates lysosomal hydrolases and enhances the potency of antimicrobial agents, creating conditions hostile to microbial survival.^[39] Within the phagolysosome, pathogen killing occurs through both oxygen-dependent and oxygen-independent mechanisms. The oxygen-dependent pathway, prominent in neutrophils and macrophages, relies on the phagocyte NADPH oxidase complex (NOX2), which assembles upon phagosome activation to generate superoxide anion (O2•−) from molecular oxygen and NADPH.^[40] Superoxide is rapidly converted to hydrogen peroxide (H2O2), which myeloperoxidase (MPO) then uses to produce hypochlorous acid (HOCl), a potent oxidant that damages microbial proteins, lipids, and DNA.^[41] This process, known as the respiratory burst, dramatically increases oxygen consumption and is essential for efficient killing of catalase-negative bacteria.^[42] Complementing the oxidative burst, oxygen-independent mechanisms involve granule-derived antimicrobial proteins and enzymes released into the phagolysosome. These include lysozyme, which hydrolyzes bacterial peptidoglycan; defensins, small cationic peptides that disrupt microbial membranes; cationic proteins like bactericidal/permeability-increasing protein (BPI); and lactoferrin, which sequesters iron to starve pathogens.^[43] These agents provide robust killing even in anaerobic conditions or in phagocytes with impaired oxidative function, such as those in chronic granulomatous disease.^[44] Once killing is achieved, digestion proceeds via hydrolytic enzymes within the phagolysosome, breaking down microbial remnants into soluble components for nutrient recycling. Key enzymes include cathepsins (aspartic and cysteine proteases that degrade proteins), DNases (which fragment nucleic acids), and other hydrolases such as lipases and glycosidases.^[38] This enzymatic degradation not only eliminates threats but also allows phagocytes to extract amino acids, nucleotides, and lipids for their own metabolic needs and antigen presentation.^[45] The efficiency of intracellular killing varies by phagocyte type; for instance, neutrophils exhibit a particularly intense respiratory burst, enabling rapid destruction of engulfed particles within minutes.^[42] While the focus here is on intracellular processes, neutrophils can also deploy neutrophil extracellular traps (NETs) as an alternative extracellular killing strategy, involving the release of chromatin and antimicrobial proteins.^[40]

Phagocyte Activation and Mobility

Activation Pathways

Phagocytes are primed for activation through various exogenous and endogenous signals that enhance their functional readiness. Cytokines such as interferon-gamma (IFN-γ) serve as key priming agents, binding to receptors on phagocytes to initiate intracellular signaling that promotes pro-inflammatory states, particularly in macrophages. Pathogen-associated molecular patterns (PAMPs), like lipopolysaccharide (LPS) from Gram-negative bacteria, bind to Toll-like receptors (TLRs), such as TLR4, triggering rapid immune responses in both macrophages and neutrophils.^[46] Similarly, damage-associated molecular patterns (DAMPs), including high-mobility group box 1 (HMGB1) and ATP released from stressed or necrotic cells, act as danger signals that engage pattern recognition receptors (PRRs) like TLRs and NLRP3 inflammasomes, amplifying phagocyte alertness without direct infection. Upon signal recognition, phagocytes activate distinct intracellular pathways that drive transcriptional and metabolic reprogramming. The NF-κB pathway, activated via TLR signaling or cytokine receptors, translocates to the nucleus to upregulate pro-inflammatory genes, fostering a cytotoxic phenotype in activated phagocytes. In macrophages, IFN-γ engages the JAK-STAT1 axis, promoting classical (M1) polarization by inducing expression of genes involved in antimicrobial defense. Metabolic shifts accompany these pathways; for instance, M1-like activation upregulates glycolysis and the pentose phosphate pathway to support rapid energy demands and biosynthesis, contrasting with oxidative phosphorylation favored in alternative (M2) states.^[46] Activation outcomes include enhanced expression of surface receptors, such as scavenger receptors and MHC class II molecules, which improve pathogen recognition and antigen processing. Increased production of reactive oxygen species (ROS) via NADPH oxidase assembly bolsters intracellular killing capabilities in primed phagocytes. Macrophages exhibit polarization plasticity, with M1 states (pro-inflammatory, antitumor) driven by IFN-γ and LPS, versus M2 states (anti-inflammatory, tissue repair) induced by IL-4 or IL-10. Research indicates this spectrum's adaptability in tumor microenvironments, where metabolic interventions can shift tumor-associated macrophages toward antitumor phenotypes.^[47] In neutrophils, activation yields rapid, transient responses—often within seconds—characterized by intense ROS bursts and degranulation, differing from the sustained, adaptable activation in macrophages that supports prolonged inflammation resolution.^[48]

Migration and Chemotaxis

Phagocytes exhibit chemotaxis, the directed migration toward sites of infection or injury along chemical gradients established by soluble chemoattractants such as complement component C5a, leukotriene B4 (LTB4), and N-formyl-methionyl-leucyl-phenylalanine (fMLP).^[49]^[50]^[51] These molecules, released by pathogens, damaged cells, or activated immune components, create concentration gradients that guide phagocytes from the bloodstream or surrounding tissues to the target area.^[52] The process is mediated by G-protein-coupled receptors (GPCRs) on the phagocyte surface, including formyl peptide receptor 1 (FPR1), which specifically binds formylated peptides like fMLP derived from bacteria.^[53] Upon ligand binding, these receptors activate intracellular signaling cascades involving heterotrimeric G-proteins, leading to cytoskeletal polarization essential for motility.^[54] Actin polymerization is enriched at the leading edge, forming lamellipodia or filopodia that propel the cell forward, while myosin II contracts at the rear uropod to facilitate retraction and maintain directionality.^[55]^[56] In tissues, phagocytes navigate complex environments through diapedesis, the transmigration across endothelial barriers, primarily via homophilic interactions between platelet endothelial cell adhesion molecule-1 (PECAM-1) on leukocytes and endothelial cells, which destabilize junctions to allow passage without disrupting the barrier integrity.^[57]^[58] To penetrate the extracellular matrix (ECM), phagocytes secrete matrix metalloproteinases (MMPs), such as MT1-MMP, which degrade ECM components like collagen and fibronectin, creating paths for interstitial migration.^[59]^[60] Migration speed is tightly regulated, with neutrophils typically moving at 10-20 μm/min in response to gradients, balancing rapid recruitment with coordinated tissue traversal.^[61] Recent intravital imaging studies from 2022 have revealed swarm behavior in tissues, where lead neutrophils amplify signals to recruit followers, enabling collective migration and efficient containment of infections through amplified chemotactic relays.^[62]^[63] This motility is often triggered following phagocyte activation, integrating with broader immune responses.^[64]

Types of Phagocytes

Monocytes and Macrophages

Monocytes are circulating mononuclear phagocytes that primarily originate from hematopoietic progenitors in the bone marrow. In mice, these include Ly6C-high monocytes, which serve as precursors for tissue macrophages under inflammatory conditions, while in humans, CD14-positive monocytes represent a key subset with similar roles.^[65] Upon recruitment to tissues, monocytes differentiate into macrophages, which are long-lived, tissue-resident professional phagocytes adapted to specific microenvironments. For instance, in the lungs, they become alveolar macrophages that maintain pulmonary homeostasis, while in the liver, they develop into Kupffer cells responsible for clearing blood-borne pathogens and debris. This differentiation is influenced by local growth factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) for alveolar macrophages. Bone marrow-derived monocytes can also contribute to self-renewing macrophage populations in adult tissues when embryonic-derived cells are depleted.^[66]^[67]^[68] Macrophages perform essential functions in long-term immune surveillance, patrolling tissues for pathogens and damaged cells, and engaging in efferocytosis—the phagocytosis of apoptotic cells—to prevent inflammation and promote resolution. They secrete cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), particularly in pro-inflammatory states, to orchestrate immune responses. Macrophages exhibit functional polarization, adopting M1-like phenotypes for antimicrobial activity and M2-like phenotypes for tissue repair and anti-inflammatory effects, driven by environmental cues.^[66]^[69]^[70] A hallmark of macrophages is their high plasticity, allowing phenotypic shifts in response to stimuli, and their capacity for self-renewal within tissues, independent of continuous monocyte influx under steady-state conditions. Recent studies from 2023 onward have highlighted epigenetic modifications in monocytes that persist after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, contributing to dysregulated responses in long COVID and other chronic inflammatory diseases. In terms of phagocytic capacity, macrophages efficiently engulf large particles, such as bacteria or apoptotic bodies, but operate at a slower rate compared to neutrophils, emphasizing their role in sustained rather than acute clearance.^[71]^[67]^[72]

Neutrophils

Neutrophils are the most abundant type of circulating leukocytes, comprising 50% to 70% of the total white blood cell count in healthy adults.^[73] These granulocytes are characterized by a multilobular nucleus, typically segmented into 2 to 5 lobes connected by thin filaments, which facilitates their deformability during migration through tissues.^[74] Neutrophils contain distinct granule populations, including azurophilic (primary) granules that store antimicrobial enzymes like myeloperoxidase and defensins, and specific (secondary) granules that hold lactoferrin, lysozyme, and neutrophil gelatinase-associated lipocalin for targeted release during immune responses.^[75] As key effectors in acute inflammation, neutrophils rapidly respond to infection sites through chemotaxis and adhesion, where they perform phagocytosis to engulf and destroy bacteria and fungi.^[76] Upon pathogen contact, they generate a potent oxidative burst via NADPH oxidase, producing reactive oxygen species (ROS) such as superoxide and hydrogen peroxide to damage microbial targets, with this process being more intense in neutrophils compared to other phagocytes due to their high enzyme content.00830-8) Additionally, neutrophils release neutrophil extracellular traps (NETs), web-like structures composed of decondensed chromatin fibers decorated with antimicrobial proteins like histones, elastase, and myeloperoxidase, which trap and kill extracellular pathogens without requiring engulfment.^[77] The lifecycle of neutrophils is short and tightly regulated to prevent excessive inflammation. Mature neutrophils have a circulating half-life of approximately 4–18 hours under homeostatic conditions, with total lifespan estimated at up to 5.4 days. In tissues during inflammation, their functional activity can persist for several days.^[78] Following pathogen clearance, activated neutrophils undergo apoptosis, a programmed cell death process that signals for their recognition and efferocytosis by macrophages, thereby resolving inflammation and avoiding tissue damage from prolonged activity.^[79] Recent research highlights the dual role of neutrophils in pathology, particularly through dysregulated NET formation. In autoimmune conditions like systemic lupus erythematosus (SLE), excessive NETs contribute to disease progression by promoting autoantibody production and vascular inflammation, as evidenced by elevated NET levels correlating with lupus flares in studies from 2021 onward.^[80] This underscores neutrophils' involvement in both protective immunity and potential autoimmunity when their antimicrobial mechanisms are unchecked.^[76]

Dendritic Cells

Dendritic cells represent a specialized class of professional phagocytes that link innate and adaptive immunity by capturing, processing, and presenting antigens to initiate targeted T-cell responses. Originating from hematopoietic stem cells in the bone marrow, they differentiate into distinct lineages that patrol peripheral tissues in an immature state, actively surveying for pathogens and damaged cells. Upon activation, these cells undergo maturation, migrating to lymphoid organs to orchestrate immune priming, thereby distinguishing them from other phagocytes focused primarily on immediate microbial clearance. Dendritic cells encompass several subtypes, including conventional dendritic cells (cDCs) divided into cDC1 and cDC2 subsets, as well as plasmacytoid dendritic cells (pDCs). cDC1s specialize in cross-presenting antigens via MHC class I to activate CD8⁺ T cells, while cDC2s primarily present antigens on MHC class II to stimulate CD4⁺ T cells; pDCs, in contrast, excel at producing type I interferons in response to viral threats. All subtypes arise from common bone marrow precursors, such as common dendritic cell progenitors (CDPs), which commit to either cDC or pDC lineages through transcription factors like IRF8 and BATF3 for cDC1s.^[81]^[82] A core function of dendritic cells involves antigen sampling in peripheral tissues through macropinocytosis, an actin-driven process that enables the non-specific uptake of extracellular fluid, soluble proteins, and particulates for subsequent processing. Following engulfment, antigens are degraded in endolysosomal compartments and loaded onto MHC class II molecules. Activated dendritic cells then migrate to lymph nodes via upregulation of CCR7, a chemokine receptor that guides them to T-cell zones, where they present peptide-MHC complexes to prime naive T cells and direct their differentiation into effector subsets.^[83]00455-X) Immature dendritic cells exhibit exceptionally high endocytic capacity, far surpassing that of other antigen-presenting cells, which facilitates broad environmental surveillance. Maturation is triggered by Toll-like receptor (TLR) ligation, where pathogen-derived ligands bind TLRs to activate signaling cascades like NF-κB, leading to profound phenotypic changes. This includes downregulation of endocytic receptors and upregulation of costimulatory molecules such as CD80 and CD86, which provide signal 2 to T cells for full activation, alongside increased MHC class II expression for enhanced antigen display.00449-4)^[84]^[85] Recent single-cell RNA sequencing studies from 2023 have illuminated dendritic cell heterogeneity, revealing diverse transcriptional states within tumor-infiltrating subsets that influence vaccine efficacy and cancer immunotherapy outcomes. For example, analyses in non-small cell lung cancer and hepatocellular carcinoma identified cDC2 subpopulations with pro- versus anti-inflammatory profiles, correlating with anti-PD-1 response rates and guiding subset-specific targeting in therapeutic vaccines. These insights underscore the functional diversity of dendritic cells, enabling tailored strategies to boost antitumor immunity.^[86]^[87]

Other Professional Phagocytes

In addition to the primary types, other cells exhibit professional phagocytic activity. Eosinophils, granulocytes derived from bone marrow, perform phagocytosis primarily against parasitic helminths and allergens, releasing cytotoxic granules and producing ROS, though with lower efficiency compared to neutrophils. Osteoclasts, multinucleated cells differentiated from monocyte-macrophage lineage, specialize in bone resorption by phagocytosing mineralized bone matrix and debris, playing a key role in skeletal remodeling and calcium homeostasis. These cells express phagocytic receptors like Fcγ and complement receptors, contributing to specialized immune and tissue maintenance functions.^[1]^[88]

Non-Professional Phagocytes

Non-professional phagocytes are tissue-resident cells that engage in phagocytosis opportunistically, primarily to maintain local homeostasis rather than as a dedicated immune function. These cells, including epithelial cells, fibroblasts, and endothelial cells, exhibit limited phagocytic capacity compared to professional phagocytes like macrophages and neutrophils, which possess specialized machinery for pathogen engulfment and destruction.^[89]^[2] Epithelial cells in the gut and lungs, for instance, uptake cellular debris and apoptotic bodies to support barrier integrity, while fibroblasts at wound sites clear extracellular matrix remnants, and endothelial cells handle vascular cleanup of senescent red blood cells or microthrombi. Smooth muscle cells in the vasculature also act as non-professional phagocytes, engulfing apoptotic neighbors during atherosclerosis progression. These activities rely on a restricted set of receptors, such as integrins (e.g., αvβ3) and CD36, which recognize "eat-me" signals like phosphatidylserine on target cells, but with efficiencies typically below 10-15% in vitro, far lower than professional counterparts. Unlike immune-specialized cells, non-professional phagocytes lack robust intracellular killing mechanisms, such as potent lysosomal enzymes or reactive oxygen species production tailored for microbial destruction, limiting their role to non-infectious debris.^[89]^[90]^[91] In physiological contexts, these cells contribute to tissue homeostasis by preventing the accumulation of necrotic material that could disrupt organ function, such as in lung epithelial clearance of surfactant-laden debris or intestinal epithelial efferocytosis to sustain barrier function. Pathologically, smooth muscle cell-mediated efferocytosis in atherosclerotic plaques helps mitigate inflammation by removing apoptotic cells, reducing necrotic core formation and plaque instability when efficient. Emerging research highlights roles in microbiome interactions, where neonatal intestinal epithelial cells efferocytose Salmonella-infected enterocytes, potentially modulating gut microbiota composition by limiting pathogen dissemination and inflammation without adult-like shedding mechanisms.^[89]^[91]^[90] However, the limited capacity of non-professional phagocytes makes them susceptible to overload in chronic conditions, where excessive apoptotic burden can lead to incomplete clearance and granuloma formation as a compensatory response. In atherosclerosis, impaired efferocytosis by these cells due to factors like oxidized lipids or clonal expansion exacerbates plaque vulnerability. Similarly, in microbiome contexts, age-dependent inefficiencies in epithelial phagocytosis may allow transient pathogen persistence, underscoring their auxiliary rather than primary defensive role.^[89]^[91]^[90]

Immune Interactions

Role in Apoptosis Clearance

Phagocytes play a crucial role in efferocytosis, the specialized process of recognizing, engulfing, and degrading apoptotic cells to maintain tissue homeostasis without triggering inflammation.^[92] This clearance is mediated by "eat-me" signals on apoptotic cells, such as the externalization of phosphatidylserine (PS) on the plasma membrane, which binds to receptors like TIM-4 and stabilin-2 on phagocytes to initiate engulfment.^[30] Another key signal is the exposure of calreticulin on the cell surface, which activates the low-density lipoprotein receptor-related protein (LRP) on phagocytes via trans-activation, facilitating rapid uptake.^[93] Following engulfment, phagocytes process the apoptotic cargo in lysosomes, preventing the release of intracellular contents that could provoke immune responses. Efferocytosis also induces anti-inflammatory signaling in phagocytes, promoting the production of immunosuppressive cytokines such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), which dampen pro-inflammatory pathways and support resolution of inflammation.^[94] Macrophages serve as the primary effectors of efferocytosis, efficiently clearing apoptotic cells in tissues, while neutrophils and dendritic cells provide supplementary assistance, particularly in dynamic environments like inflamed sites.^[95]^[96]^[97] In humans, this process clears approximately 200–300 billion apoptotic cells daily, underscoring its scale in preserving immune tolerance.^[92] The importance of efferocytosis lies in its ability to prevent secondary necrosis of uncleared apoptotic cells, which would otherwise release damage-associated molecular patterns (DAMPs) and trigger chronic inflammation or autoimmunity.^[98] Defects in this process are implicated in autoimmune disorders, notably systemic lupus erythematosus (SLE), where impaired clearance leads to accumulation of apoptotic debris and autoantibody production against nuclear antigens.^[99] Recent 2022 studies have highlighted efferocytosis's dual role in inflammation resolution and cancer; for instance, it promotes anti-inflammatory reprogramming in resolving tissues, but in tumors, efferocytosis by tumor-associated macrophages (TAMs) can drive M2-like polarization, fostering an immunosuppressive microenvironment that supports tumor growth and metastasis.^[100] Interventions like thymosin α1 have been shown to reverse this M2 polarization during efferocytosis, enhancing anti-tumor immunity.^[100]

Antigen Presentation

Phagocytes, particularly dendritic cells (DCs) and macrophages, play a crucial role in bridging innate and adaptive immunity by processing engulfed antigens and presenting peptide fragments on major histocompatibility complex (MHC) molecules to T lymphocytes.^[101] Following phagocytosis, antigens are internalized into phagosomes, where they undergo degradation by lysosomal proteases such as cathepsins, generating peptides suitable for MHC loading.^[101] These peptides are then loaded onto MHC class II molecules in endosomal compartments for presentation to CD4+ T cells, or, in the case of cross-presentation, onto MHC class I molecules for CD8+ T cell activation.^[102] In MHC class II presentation, newly synthesized MHC II molecules associate with the invariant chain (Ii, also known as CD74) in the endoplasmic reticulum to prevent premature peptide binding and direct the complex to phagosomal or MHC class II-rich compartments (MIIC).^[101] There, Ii is proteolytically degraded, leaving a CLIP fragment that is exchanged for antigenic peptides with the aid of HLA-DM, enabling stable MHC II-peptide complexes to traffic to the cell surface.^[101] For MHC class I presentation of exogenous phagosomal antigens, cross-presentation is predominant in DCs, where antigens escape to the cytosol for proteasomal degradation, and resulting peptides are transported via the transporter associated with antigen processing (TAP) into the endoplasmic reticulum or phagosomes for loading onto recycled MHC I molecules.^[102] This process often involves ER-phagosome fusion mediated by proteins like Sec22b, enhancing efficiency in professional antigen-presenting cells.^[101] Dendritic cells are the primary phagocytes specialized for antigen presentation, particularly cross-presentation by the cDC1 subset, which efficiently primes naive CD8+ T cells against intracellular pathogens and tumors.^[102] Macrophages serve a secondary role, capable of cross-presentation via vacuolar or cytosolic pathways but generally less effective at priming naive T cells compared to DCs, often supporting reactivation of memory T cells or antigen transfer to DCs.^[103] TAP recruitment to phagosomes in DCs further boosts MHC I peptide supply, while the invariant chain ensures targeted MHC II loading, optimizing overall presentation efficiency.^[101] Effective T cell activation requires not only MHC-peptide display but also costimulatory signals, such as the interaction between B7 molecules (CD80 and CD86) on phagocytes and CD28 on T cells, which promotes T cell proliferation and survival.^[104] DCs upregulate B7 upon maturation, providing robust costimulation, whereas macrophages offer variable levels depending on their activation state.^[105] The cytokine environment further shapes responses; for instance, IL-12 secreted by DCs during antigen presentation drives Th1 differentiation and IFN-γ production by CD8+ T cells, enhancing cytotoxic immunity.^[106] Recent advances, including cryo-electron microscopy (cryo-EM) structures post-2018, have illuminated the MHC I peptide-loading complex (PLC) in atomic detail, revealing how tapasin and associated chaperones like ERp57 and calreticulin edit peptides for high-affinity binding in professional APCs such as DCs.^[107] These insights, derived from 9.9-Å cryo-EM densities combined with molecular dynamics simulations, demonstrate the PLC's layered architecture and glycan-mediated stabilization, underscoring mechanisms that fine-tune cross-presentation efficiency in phagocytes.^[107]

Contribution to Immunological Tolerance

Phagocytes play a crucial role in maintaining immunological tolerance by suppressing aberrant immune responses against self-antigens and harmless environmental antigens, thereby preventing autoimmunity and chronic inflammation. Regulatory dendritic cells (DCs) contribute to this process by presenting self-antigens in the context of low costimulatory signals, such as reduced expression of CD80 and CD86, which promotes T cell anergy or deletion rather than activation.^[108]^[109] Similarly, macrophages secrete immunosuppressive cytokines like interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which dampen effector T cell responses and foster regulatory T cell (Treg) expansion to enforce peripheral tolerance.^[110]^[111] These mechanisms also facilitate the peripheral deletion of autoreactive T cells through phagocyte-mediated apoptosis induction or cross-presentation of self-antigens in a tolerogenic manner.^[112] Specific subtypes of phagocytes are specialized for tolerance induction. Tolerogenic DCs, particularly the CD103+ subset in mucosal tissues, excel at capturing and presenting antigens from apoptotic cells or commensals while maintaining an immature phenotype that limits costimulation and promotes Treg differentiation via retinoic acid production.^[113]^[114] M2-polarized macrophages, characterized by their anti-inflammatory profile, further support tolerance by enhancing IL-10 and TGF-β secretion in response to steady-state signals, thereby resolving inflammation and maintaining tissue homeostasis without excessive immune activation.^[115]^[116] In physiological contexts, phagocytes uphold tolerance through steady-state efferocytosis—the efficient clearance of apoptotic cells—which prevents the release of pro-inflammatory damage-associated molecular patterns and sustains an anti-inflammatory milieu via IL-10 and TGF-β upregulation.^[117] In the gut, mononuclear phagocytes, including CD103+ DCs and resident macrophages, interact with commensal bacteria to induce tolerance, sampling luminal antigens and driving Foxp3+ Treg generation to avert responses against the microbiota.^[118] Defects in these phagocyte functions disrupt tolerance, contributing to diseases such as inflammatory bowel disease (IBD), where impaired efferocytosis and dysregulated cytokine production lead to chronic mucosal inflammation, and allergies, arising from failed suppression of Th2 responses to environmental antigens.^[119]^[120]^[121] Recent advances highlight the therapeutic potential of phagocyte-derived exosomes in tolerance induction. Studies from 2024 demonstrate that dendritic cell exosomes loaded with tolerogenic signals, such as TGF-β, promote Treg expansion and suppress allograft rejection in transplant models, offering a non-cellular approach to achieve long-term immune tolerance without broad immunosuppression.^[122] Similarly, M2 macrophage-derived exosomes have been engineered to deliver miRNA cargos that modulate T cell reactivity, enhancing antigen-specific tolerance in autoimmune and transplant settings.^[123]

Pathogen Evasion Strategies

Avoiding Initial Contact

Pathogens have evolved multiple strategies to evade initial detection and approach by phagocytes, thereby delaying the onset of phagocytosis and allowing time for replication or dissemination. These pre-contact evasion tactics primarily target pattern recognition receptors (PRRs) on phagocytes, such as Toll-like receptor 4 (TLR4), and disrupt signaling pathways that mediate chemotaxis and recruitment. By masking pathogen-associated molecular patterns (PAMPs) or mimicking host structures, microbes prevent the activation of innate immune responses that would otherwise draw phagocytes to the infection site.^[39] One prominent tactic is the production of polysaccharide capsules, which physically shield surface PAMPs from recognition by phagocyte receptors and complement proteins. For instance, the thick capsule of Streptococcus pneumoniae sterically hinders the deposition of C3b opsonins on the bacterial surface, thereby inhibiting binding to complement receptors on neutrophils and macrophages. This capsule not only reduces opsonophagocytosis but also limits the exposure of lipoteichoic acid and other PAMPs, delaying phagocyte activation. Similarly, capsules in other pathogens like Haemophilus influenzae serve as a non-immunogenic barrier that impairs initial contact.^[124]^[125] Biofilm formation represents another key strategy, particularly in chronic infections, where extracellular polymeric substances create a protective matrix that sequesters bacteria from circulating phagocytes. In the lungs, Pseudomonas aeruginosa forms biofilms during cystic fibrosis exacerbations, which attenuate neutrophil chemotaxis and phagocytosis by limiting oxygen availability and releasing quorum-sensing molecules that suppress immune signaling. These biofilms embed bacteria in a viscous environment that physically impedes phagocyte penetration and reduces PAMP exposure, allowing persistent colonization despite robust innate responses.^[126]^[127]^[128]^[129] Molecular mimicry further enables pathogens to blend with host tissues, avoiding PRR-mediated detection. Bacterial proteins or glycans that structurally resemble host molecules can inhibit complement activation and phagocyte recognition; for example, certain streptococcal surface proteins mimic eukaryotic extracellular matrix components, reducing opsonization and chemotactic signals. This mimicry exploits host tolerance mechanisms, preventing the inflammatory cues that recruit monocytes and neutrophils.^[130]^[131]^[132] Pathogens also actively disrupt phagocyte migration through mechanisms that inhibit chemotaxis signals. Many bacteria secrete factors that interfere with G-protein-coupled receptor (GPCR) pathways, such as chemokines or formyl peptide receptors, thereby blocking the directional movement of neutrophils toward infection sites. For example, Staphylococcus aureus produces chemotaxis-inhibitory proteins that bind and neutralize host chemoattractants, reducing phagocyte accumulation at early infection stages. Complementing this, some pathogens shed decoy antigens or surface components to distract phagocytes, diverting their attention to soluble mimics rather than the viable bacteria. These decoys, often released as vesicles or fragments, bind complement or antibodies, exhausting local immune resources before phagocytes reach the pathogen core.^[133] A well-documented example is Yersinia pestis, the causative agent of plague, which modifies its lipopolysaccharide (LPS) structure during mammalian infection to evade TLR4 recognition. At 37°C, Y. pestis produces tetra-acylated lipid A, a hypoacylated form that binds poorly to the TLR4/MD-2 complex on macrophages and dendritic cells, suppressing proinflammatory cytokine production and subsequent phagocyte recruitment. This LPS alteration allows the bacterium to disseminate systemically with minimal initial immune interference, underscoring the evolutionary pressure on pathogens to fine-tune surface molecules for stealth.^[134]^[135]^[136]^[137] Collectively, these evasion strategies significantly delay phagocyte recruitment, enabling pathogens to establish footholds in host tissues. By impeding the rapid influx of neutrophils and macrophages, microbes prolong the window for replication, often leading to overwhelming infections if adaptive immunity is not swiftly engaged.^[39]^[138]^[133]

Resistance to Engulfment

Pathogens employ various strategies to resist engulfment by phagocytes once initial contact has been established, thereby preventing internalization and subsequent degradation. These mechanisms target the actin cytoskeleton dynamics, phagocytic receptor engagement, and phagosome formation processes essential for particle uptake. By interfering with these steps, pathogens can evade capture and persist in the host environment.^[139] One prominent strategy involves the secretion of anti-phagocytic surface factors that recruit host complement regulators to inhibit opsonization and receptor-mediated uptake. For instance, the M protein on Streptococcus pyogenes binds complement factor H, a negative regulator of the alternative complement pathway, thereby reducing C3b deposition and subsequent complement receptor engagement on phagocytes. This interaction occurs via the central conserved C-repeat region of M protein, enhancing bacterial survival in non-immune human blood.^[140] Similarly, the fibrinogen-binding M1 protein of group A Streptococcus sequesters host fibrinogen, preventing its role in opsonization and further impeding Fc receptor activation during attempted engulfment.^[141] Pathogens also disrupt cytoskeletal rearrangements critical for pseudopod extension and phagosome closure. In Salmonella enterica, the type III secretion system effector SopE acts as a guanine nucleotide exchange factor (GEF) for Rho GTPases such as Cdc42 and Rac1, initially promoting actin polymerization to facilitate bacterial invasion of non-phagocytic cells; however, coordinated action with the GTPase-activating protein SptP subsequently deactivates these pathways, limiting full phagocytic commitment in professional phagocytes and allowing partial escape from engulfment.^[142] This manipulation exploits the host's actin regulatory network to subvert complete internalization.^[143] Receptor interference represents another key tactic, where pathogens directly block phagocytic receptors to halt signaling cascades leading to engulfment. Staphylococcus aureus produces protein A, which binds the Fc region of IgG antibodies, sterically hindering interaction with Fcγ receptors on phagocytes and thereby inhibiting opsonin-dependent uptake. This binding prevents the conformational changes in IgG necessary for effective receptor crosslinking and actin recruitment. Complement receptors can similarly be targeted; for example, capsular polysaccharides of bacteria like Streptococcus pneumoniae mask surface epitopes, reducing C3b opsonization and complement receptor 1/3 engagement.^[139] Specific examples illustrate how pathogens arrest phagosome formation mid-process. Mycobacterium tuberculosis employs multiple effectors, including the protein tyrosine phosphatase PtpA, to interfere with host Rab GTPases and prevent phagosome-lysosome fusion precursors during early engulfment, effectively stalling closure and maturation from within the forming vacuole. This allows the bacterium to reside in an immature phagosomal compartment resistant to acidification.^[144] Viruses have evolved analogous evasion tactics, often through accessory proteins that alter host cell surfaces or phagocyte function post-contact. The HIV-1 Nef protein inhibits phagocytosis in infected macrophages by disrupting the focal delivery of recycling endosomes to the phagocytic cup, thereby impairing actin remodeling and pseudopod progression around viral particles or infected debris. This Nef-dependent mechanism reduces the efficiency of engulfment by up to 70% in primary human macrophages.^[145] These resistance strategies often arise through evolutionary adaptations, including horizontal gene transfer (HGT) of anti-phagocytic loci among bacterial pathogens. In Streptococcus pyogenes, HGT contributes to variability in genes encoding M-like proteins such as PrtF1, which bind plasminogen and inhibit complement activation, facilitating rapid dissemination of resistance traits across strains. Such transfers, mediated by phages or plasmids, underscore the dynamic evolution of phagocyte evasion in microbial communities.^[146]

Survival and Counterattack Inside Phagocytes

Once internalized within phagocytes, pathogens deploy diverse strategies to evade degradation by blocking phagosome maturation and neutralizing antimicrobial defenses. A key survival mechanism is the inhibition of phagolysosome fusion, which deprives the phagosome of hydrolytic enzymes and low pH required for pathogen destruction. Legionella pneumophila, for example, utilizes its Dot/Icm type IV secretion system to inject over 300 effector proteins, including Sid family members like SidC and SidF, that remodel host membrane trafficking pathways and prevent fusion with lysosomes, thereby creating a replicative niche known as the Legionella-containing vacuole (LCV). This system is essential for intracellular replication, as mutants defective in Dot/Icm effectors exhibit restored phagolysosomal fusion and reduced bacterial viability.^[147]^[148]^[149] Pathogens also counteract the phagocyte's oxidative burst by scavenging reactive oxygen species (ROS). Salmonella enterica serovar Typhimurium expresses periplasmic superoxide dismutases SodCI and SodCII, which convert superoxide radicals into less toxic hydrogen peroxide, enabling bacterial survival against NADPH oxidase-derived ROS in the phagosome. These enzymes are critical during infection, as their absence significantly impairs S. Typhimurium persistence in macrophages and reduces virulence in vivo.^[150]^[151] To actively counterattack, certain pathogens release toxins that compromise phagosomal integrity and promote escape to the cytosol. Listeria monocytogenes secretes listeriolysin O (LLO), a pH-sensitive pore-forming cytolysin that oligomerizes in the acidic phagosomal membrane to create pores, allowing cytosolic release and subsequent actin-based motility for cell-to-cell spread. Recent structural analyses have identified specific amino acid residues in LLO that enhance pore stability and escape efficiency, underscoring its role in pathogenicity. LLO activity is tightly regulated to avoid premature host cell lysis, peaking at phagosomal pH levels around 5.5–6.0.^[152]^[153]^[154] Induction of host cell apoptosis represents another counterattack strategy, disrupting phagocyte function and potentially facilitating pathogen dissemination. Mycobacterium tuberculosis triggers caspase-3-dependent apoptosis in alveolar macrophages, which may limit bacterial spread by containing infected cells while promoting antigen presentation to T cells. Similarly, L. pneumophila via Dot/Icm effectors induces early apoptosis in macrophages, aiding evasion of innate immunity.^[155]^[149] Protozoan pathogens like Leishmania spp. exemplify long-term intracellular persistence by modifying the parasitophorous vacuole (PV), a specialized phagosome that supports amastigote replication. Leishmania amazonensis sabotages host SUMOylation pathways within the PV, suppressing innate immune signaling and preventing full lysosomal fusion, thus maintaining a nutrient-rich, non-degradative environment. This adaptation allows chronic infection, with PV pH stabilized near neutrality to favor parasite survival.^[156]^[157] Advancements in genetic screening have illuminated host-pathogen dynamics in phagosomal escape. A 2024 study using CRISPR/Cas9 knockout in bone marrow-derived macrophages demonstrated that PDCD6 negatively regulates LC3-associated phagocytosis during L. monocytogenes infection, with its depletion enhancing ROS production, trapping more bacteria in phagosomes, and reducing cytosolic replication. Such screens reveal lactate metabolism's role in modulating phagosomal defenses, offering insights into therapeutic targeting.^[158] For persistent infections, pathogens like M. tuberculosis enter latency within granulomatous structures, where dormant bacilli reside in modified phagocytes, resisting sterilizing immunity through downregulated metabolism and immune evasion. Granulomas encapsulate bacteria in foamy macrophages, enabling decades-long persistence without active replication.^[159]^[160]

Additional Aspects

Phagocyte-Induced Host Damage

Phagocytes, particularly neutrophils and macrophages, can inflict significant collateral damage to host tissues through the overproduction of reactive oxygen species (ROS) and proteases during inflammatory responses. The NADPH oxidase complex in phagocytes generates ROS to kill pathogens, but excessive release can oxidize lipids, proteins, and DNA in surrounding cells, leading to endothelial dysfunction and tissue necrosis. Similarly, proteases such as neutrophil elastase are secreted to degrade bacterial components, yet unchecked activity degrades extracellular matrix proteins like elastin and collagen, contributing to structural damage in organs such as the lungs. In chronic obstructive pulmonary disease (COPD), including emphysema, neutrophil elastase from activated phagocytes exacerbates alveolar destruction by overwhelming antiprotease defenses like alpha-1 antitrypsin.^[161]^[162]^[163]^[164] In acute settings like sepsis, dysregulated phagocytes drive cytokine storms, where macrophages and neutrophils release excessive pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, amplifying systemic inflammation and causing multi-organ failure. This hyperactivation leads to vascular leakage, hypotension, and disseminated intravascular coagulation, with phagocyte-derived mediators directly contributing to endothelial injury. Chronic inflammatory conditions, such as rheumatoid arthritis (RA), feature persistent synovial infiltration by macrophages that sustain inflammation through ROS and cytokine production, eroding cartilage and bone via matrix metalloproteinases and osteoclast activation. Post-ischemic reperfusion injury further exemplifies this, as recruited neutrophils produce ROS upon reoxygenation, exacerbating myocardial or cerebral damage through oxidative stress and impaired microvascular perfusion.^[165]^[166]^[167]^[168]^[169]^[170] Genetic dysregulation of phagocyte function, as seen in chronic granulomatous disease (CGD), arises from NADPH oxidase deficiencies that impair ROS production for pathogen killing, resulting in persistent infections and granuloma formation from uncontrolled inflammation. In CGD, defective superoxide generation leads to granulomatous damage in lungs, liver, and gastrointestinal tract. Therapeutic strategies target these pathways; for instance, anti-TNF agents like infliximab reduce macrophage-driven inflammation in RA by inhibiting TNF signaling, thereby limiting cytokine amplification and joint destruction. As of 2024, research has identified persistent immune dysregulation in long COVID, including activation of myeloid cells such as macrophages, contributing to sustained low-grade inflammation and cytokine production, with links to symptoms including fatigue and cardiopulmonary sequelae months post-infection.^[171]^[172]^[173]^[174]^[175]

Evolutionary Origins

Phagocytosis emerged as a defining feature of eukaryotic cells, predating the evolution of adaptive immunity by billions of years and appearing in the last eukaryotic common ancestor (LECA), estimated to have lived between 2.0 and 1.0 billion years ago.^[176] This process, involving the engulfment of particulate matter through plasma membrane invaginations, is absent in prokaryotes and is considered a hallmark of eukaryogenesis.^[176] Fossil evidence supports its ancient origins, with indirect signs of eukaryotic predation dating to approximately 1.05 billion years ago in red algae like Bangiomorpha pubescens, and more direct traces of eukaryovory from 1.15 to 0.9 billion years ago in the Shaler Supergroup.^[176] In single-celled eukaryotes such as amoebae, phagocytosis facilitated nutrient acquisition through bacterivory, with the process likely present in early protists around 2 billion years ago.^[177] Closely tied to endosymbiosis, phagocytosis is hypothesized to have enabled the acquisition of mitochondria by an archaeal host, though debates persist on whether it preceded or followed this event; Asgard archaea, potential pre-mitochondrial hosts, lack full phagocytic capability but may have used membrane protrusions for symbiont capture.^[176] The core machinery of phagocytosis exhibits remarkable conservation across eukaryotes, from protists to mammals, underscoring its fundamental role in cellular function. Key components, including actin and the Arp2/3 complex for cytoskeletal remodeling, as well as dynamin for membrane fission, trace back to the LECA and are shared widely, enabling pseudopod extension and particle internalization in diverse lineages.^[177] Actin homologs in certain archaea, such as Crenarchaeota, show monophyly with eukaryotic actins, suggesting an even deeper prokaryotic ancestry, while Rho family GTPases—crucial regulators of actin dynamics in phagocytosis—are of bacterial origin, likely acquired through horizontal gene transfer.^[177] Phagocytic receptors, however, display limited conservation, having evolved independently in various groups from ancient pattern recognition systems that detect microbial signatures, allowing adaptation to specific environmental threats.^[177] In metazoans, phagocytosis expanded as a cornerstone of innate immunity, integrating with multicellular defenses to clear pathogens and debris more efficiently than in unicellular ancestors. Comparative studies reveal this elaboration in early-diverging animals; for instance, sea urchin coelomocytes—professional phagocytes in echinoderms—express diverse scavenger receptors and perform opsonin-dependent engulfment, mirroring mammalian mechanisms while highlighting deuterostome innovations in immune surveillance. This metazoan diversification likely arose from gene family expansions, such as Toll-like receptors, which coordinate phagocytic responses in invertebrates lacking adaptive immunity.^[178] Recent genomic analyses in the 2020s have illuminated the pre-metazoan roots of phagocytic genes, particularly in choanoflagellates—the closest unicellular relatives of animals—which actively perform bacterivory via a microvillar collar, supported by conserved actin-based machinery.^[179] Sequencing of species like Salpingoeca rosetta has identified horizontal gene transfers contributing to endocytosis-related genes, bridging unicellular phagocytosis to metazoan immune evolution and revealing how these processes facilitated the transition to multicellularity.^[180]

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