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Phagocytosis

Phagocytosis is a fundamental cellular process whereby specialized cells known as phagocytes actively engulf and internalize large particulate matter, such as microorganisms, apoptotic cells, and debris exceeding 0.5 μm in diameter, through a receptor-mediated form of endocytosis.^[1] This process was first systematically described in the early 1880s by Russian immunologist Élie Metchnikoff, who observed motile cells in the larvae of starfish (Asterias rubens) ingesting foreign particles such as rose thorns, thereby establishing the concept of cellular immunity as a primary defense mechanism against infection.^[2] Metchnikoff's work, which earned him the Nobel Prize in Physiology or Medicine in 1908 (shared with Paul Ehrlich), highlighted phagocytosis as an ancient evolutionary adaptation present in both unicellular organisms and multicellular animals.^[3] Phagocytes are broadly classified into professional and non-professional types, with professional phagocytes exhibiting high efficiency in particle uptake; these include neutrophils, macrophages, monocytes, dendritic cells, and osteoclasts, all of which express an array of pattern recognition receptors to detect targets.^[4] Neutrophils, the most abundant circulating phagocytes, provide rapid responses to acute infections, while tissue-resident macrophages and dendritic cells contribute to both clearance and immune signaling.^[5] The mechanism of phagocytosis unfolds in distinct phases: initial recognition of the target via opsonin-dependent (e.g., antibodies or complement proteins) or non-opsonic receptors (e.g., scavenger or Toll-like receptors); subsequent intracellular signaling that triggers actin cytoskeleton remodeling and pseudopod extension around the particle; formation of a sealed phagosome that pinches off from the plasma membrane; and phagosome maturation, involving sequential fusion with early endosomes, late endosomes, and lysosomes to create a phagolysosome equipped with hydrolytic enzymes and reactive oxygen species for degradation.^[5] This maturation process is tightly regulated by Rab GTPases, SNARE proteins, and lipid modifications to ensure efficient killing and nutrient recycling.^[6] Beyond pathogen elimination, phagocytosis is indispensable for innate immunity, tissue homeostasis, and development, as it clears over 10^11 apoptotic cells daily in humans to avert inflammation and autoimmunity while facilitating antigen presentation to T cells for adaptive responses. Dysfunctions in phagocytic pathways are implicated in immunodeficiencies, chronic inflammatory diseases, and cancer, underscoring its broad physiological impact.^[4]

Introduction

Definition and Process Overview

Phagocytosis is an active, receptor-mediated process by which cells engulf and internalize large particles, typically greater than 0.5 μm in diameter, such as microorganisms, cellular debris, or apoptotic bodies, into a membrane-bound vesicle known as a phagosome.00611-7) This form of endocytosis enables cells to capture and process extracellular material that is too large for other uptake mechanisms.^[7] Unlike pinocytosis, which constitutively internalizes extracellular fluids and dissolved solutes in small vesicles, or receptor-mediated endocytosis, which selectively takes up specific small ligands via clathrin-coated pits, phagocytosis specifically targets solid particles and involves the protrusion of actin-driven pseudopods to surround and enclose the target.^[8] These pseudopods form a cup-like structure that progressively zips around the particle, ensuring complete enclosure without leakage.^[9] The process unfolds in a series of coordinated steps: initial recognition and attachment of the particle to the cell surface, followed by engulfment via pseudopod extension and actin remodeling; subsequent phagosome formation as the plasma membrane fuses to seal the vesicle; maturation, where the phagosome acquires lysosomal enzymes through vesicular trafficking; and finally, the destruction of internalized contents via enzymatic degradation or their recycling for cellular use.^[9] Each step ensures efficient isolation and processing of the engulfed material. Phagocytosis is fundamentally ATP-dependent, harnessing cellular energy to fuel actin polymerization and the dynamic cytoskeletal changes required for pseudopod formation and membrane invagination.^[10] This energy investment underscores its role as a targeted defense mechanism in immunity.30065-6)

Biological Significance

Phagocytosis plays a fundamental role in cellular maintenance by facilitating the clearance of apoptotic cells and debris, thereby preventing the release of intracellular contents that could trigger inflammation or tissue damage. This process, known as efferocytosis when involving apoptotic cells, is essential for tissue homeostasis and remodeling throughout the body. In unicellular organisms like amoebae, phagocytosis primarily serves as a mechanism for nutrient acquisition by engulfing bacteria and other particles, highlighting its ancient adaptive function for survival and energy procurement. Additionally, in multicellular organisms, the phagocytosis of apoptotic cells promotes immune tolerance to self-antigens through the presentation of self-derived peptides to T cells, which helps maintain peripheral tolerance and prevents autoimmunity. The process is evolutionarily conserved across eukaryotes, with evidence of its presence in early microbial life forms such as vampyrellid amoebae and other protozoa, where it likely originated as a predatory feeding strategy before evolving into a defensive mechanism in higher organisms. This conservation underscores phagocytosis's critical role in eukaryotic survival, from nutrient uptake in free-living amoebae like Dictyostelium discoideum to pathogen elimination in metazoans, suggesting it emerged during or before eukaryogenesis to enable the ingestion of large particles. Defects in phagocytosis underlie various immunodeficiencies, such as chronic granulomatous disease (CGD), where mutations in the NADPH oxidase complex impair the oxidative burst necessary for killing engulfed microbes, leading to recurrent infections. Dysregulation of phagocytosis also contributes to pathological conditions, including autoimmunity through failed clearance of apoptotic cells that exposes self-antigens and promotes inflammatory responses, and cancer, where tumor cells evade phagocytic uptake via "don't eat me" signals like CD47, allowing immune escape. In healthy adults, macrophages phagocytose approximately $10^{11} apoptotic cells daily, equivalent to the turnover of about 200–300 billion cells, illustrating the immense scale of this process in sustaining organismal health.

Molecular and Cellular Mechanisms

Recognition and Binding

Phagocytosis begins with the recognition and binding of target particles, such as pathogens or apoptotic cells, by phagocytic cells through specific receptor-ligand interactions. Opsonization enhances this process by coating particles with host-derived molecules that serve as bridges to phagocyte receptors, thereby increasing the efficiency of uptake.^[11] A primary form of opsonization involves the deposition of antibodies, particularly immunoglobulin G (IgG), onto the surface of targets, which facilitates binding to Fcγ receptors on phagocytes. Complement proteins, such as C3b generated through the classical or alternative pathways, also act as opsonins by covalently attaching to particle surfaces and promoting adhesion via complement receptors. Additionally, collectins like mannose-binding lectin (MBL) bind to carbohydrate patterns on pathogens, initiating the lectin pathway of complement activation and depositing C3b for enhanced recognition.^[12]^[13]^[14] Key receptors mediating these interactions include Fcγ receptors (FcγR), which specifically bind the Fc portion of IgG-opsonized targets and are essential for antibody-dependent phagocytosis. Complement receptor 1 (CR1) recognizes C3b and facilitates immune adherence, while complement receptor 3 (CR3, also known as CD11b/CD18) binds iC3b, a cleavage product of C3b, to promote particle internalization. Pattern recognition receptors, such as the mannose receptor (MR, or CD206), enable direct detection of microbial carbohydrates like mannose and fucose, contributing to non-antibody-mediated uptake.^[15]^[16] In addition to opsonic mechanisms, non-opsonic recognition occurs through direct binding of unopsonized particles via scavenger receptors, which capture modified lipids or polyanions on apoptotic cells and debris, and integrins like CR3, which can engage non-complement ligands such as β-glucans on fungi. These interactions allow phagocytosis in the absence of humoral opsonins, broadening the scope of target clearance.^[17] Upon binding, receptor crosslinking by multivalent ligands triggers intracellular signaling cascades that initiate phagocytic commitment. This involves activation of src family kinases, which phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) within the cytoplasmic tails of receptors like FcγR, recruiting and activating the spleen tyrosine kinase (Syk) to propagate downstream signals.^[15]

Engulfment and Actin Dynamics

Following recognition signals from particle binding, the engulfment phase of phagocytosis involves coordinated cytoskeletal rearrangements to internalize the target. This process relies on dynamic actin assembly to form pseudopods that extend the plasma membrane around the particle, creating a phagocytic cup.^[18] Pseudopod formation is driven by localized actin polymerization mediated by the Arp2/3 complex, which nucleates branched actin filaments. The WASP (Wiskott-Aldrich syndrome protein) family and Scar/WAVE proteins activate Arp2/3 at the plasma membrane, recruiting it to sites of particle attachment and generating protrusive forces that extend membrane ruffles around the target.^[19]^[20] These actin networks provide structural support and propulsion, enabling the cell to envelop particles larger than 0.5 μm in diameter.^[21] Regulation of these events is tightly controlled by Rho GTPases, small molecular switches that cycle between GTP-bound (active) and GDP-bound (inactive) states. Cdc42 and Rac1 are activated early at the phagocytic cup, where they stimulate actin nucleation through effectors like WASP and WAVE, promoting pseudopod extension and cup progression.^[18]^[22] In contrast, RhoA activation later in the process enhances myosin-mediated contractility, constricting the actin cytoskeleton to facilitate cup closure without excessive protrusion.^[18]^[23] This spatiotemporal patterning ensures efficient membrane remodeling tailored to the particle's size and shape. The pseudopods converge and fuse at the particle's base to seal the nascent phagosome, completing internalization. This fusion occurs via two primary modes: the zippering mode, characteristic of Fcγ receptor-mediated uptake, which requires extensive adhesion and contact over approximately 60-70% of the particle surface to progressively extend pseudopods; and the sinking mode, often seen with complement receptors, which involves minimal pseudopod formation and contact over about 20% of the surface as the particle is drawn inward.^[15]^[24] These modes reflect adaptations to different opsonins, optimizing energy use for varied targets. Engulfment is an energy-demanding process that typically completes in 1-5 minutes for particles around 3 μm in diameter. It consumes on the order of 10^7 to 10^8 ATP molecules per event, primarily for actin polymerization and myosin activity; cellular ATP levels drop by approximately 1 fmol per cell during active phagocytosis in professional phagocytes like neutrophils.^[25]^[26]

Phagosome Formation

Upon closure of the phagocytic cup, the phagosome forms as a discrete, single-membrane-bound vesicle that sequesters the engulfed particle from the cytosol, with its limiting membrane derived primarily from the plasma membrane. This nascent organelle initially maintains a near-neutral luminal pH of approximately 7.2, reflecting the extracellular environment, and excludes lysosomal markers such as LAMP1, distinguishing it from later degradative compartments.^[27]^[28] Early post-formation events involve selective remodeling of the phagosomal membrane, including the exclusion of specific plasma membrane proteins, such as GPI-anchored proteins and certain integrins, which are actively sorted away during cup closure to establish a specialized composition. Concurrently, the phagosome recruits early endosomal markers like EEA1 and Rab5 via homotypic fusion with early endosomes, enabling the acquisition of endocytic machinery while preserving its isolation from late endocytic pathways. Additionally, partial clearance of cortical actin occurs rapidly after sealing, driven by disassembly factors like cofilin, which disassembles the actin cytoskeleton that previously supported engulfment and allows the phagosome to detach from the plasma membrane.^[29]^[30]^[6] Phagosomes exhibit a spherical morphology with diameters typically ranging from 0.5 to 10 μm, scaled to the size of the engulfed particle—such as 1-2 μm for bacteria or larger for apoptotic cells—and their surface area expands through contributions from intracellular membrane sources during early fusions. These initial interactions with early endosomes not only provide regulatory lipids like phosphatidylinositol 3-phosphate but also support the phagosome's positioning along microtubules for subsequent trafficking. In instances of incomplete or aberrant formation, such as partial engulfment, quality control mechanisms may invoke autophagy to target and resolve the defective structure or trigger phagocyte apoptosis to eliminate compromised cells, preventing inflammatory leakage.^[31]^[4]^[32]

Maturation and Lysosomal Fusion

Following its initial formation, the phagosome undergoes a progressive maturation process that transforms it into a microbicidal organelle capable of degrading engulfed material. This maturation is divided into distinct stages marked by the sequential recruitment and exchange of Rab GTPases. The early phagosome, shortly after sealing, acquires Rab5 on its membrane, which promotes homotypic fusion with early endosomes and the recruitment of early endosomal markers such as EEA1.^[33] As maturation advances, typically within 10-30 minutes, Rab5 is replaced by Rab7 through a GTPase exchange mechanism involving the Mon1-Ccz1 complex, marking the transition to the late phagosome stage; Rab7 facilitates interactions with late endosomal compartments and is essential for subsequent acidification and fusion events.^[34] The final stage culminates in phagolysosome formation, characterized by the acquisition of lysosomal-associated membrane proteins (LAMPs), particularly LAMP-1 and LAMP-2, which stabilize the membrane and support degradative functions.^[35] A critical aspect of phagosome maturation is the progressive acidification of the internal lumen, which drops from a near-neutral pH of approximately 7.2 in the early stage to an acidic pH of 4.5-5.0 in the phagolysosome. This pH gradient is established and maintained by the vacuolar-type H+-ATPase (V-ATPase), a multi-subunit proton pump that is progressively recruited to the phagosomal membrane during the early-to-late transition; V-ATPase assembly is regulated by Rab7 and associated effectors like RILP, ensuring efficient proton translocation without excessive energy expenditure.^[36] The acidified environment activates lysosomal hydrolases and enhances the activity of antimicrobial mechanisms. Maturation involves a series of membrane fusion events orchestrated by SNARE proteins and tethering complexes. Initially, the early phagosome undergoes homotypic fusions with early endosomes via SNARE complexes involving syntaxin-6 and VAMP-3, followed by heterotypic fusions with late endosomes mediated by syntaxin-7, Vti1b, syntaxin-8, and VAMP-7 as the R-SNARE.^[37] The homotypic human organelle tethering protein (HOPS) complex, recruited by Rab7, acts as a key tethering factor that bridges phagosomes and lysosomes, promoting SNARE-mediated heterotypic fusion; VAMP-7 on lysosomes pairs with Q-SNAREs on the late phagosome (e.g., SNAP-23, syntaxin-7) to drive content mixing and delivery of lysosomal enzymes.^[38] These fusions ensure the progressive delivery of degradative components while maintaining compartmental integrity. Within the mature phagolysosome, microbial killing is achieved through multiple synergistic mechanisms. The NADPH oxidase complex (NOX2) generates reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, primarily in the early-to-late transition, creating an oxidative burst that damages microbial lipids, proteins, and DNA.^[39] Nitric oxide produced by inducible nitric oxide synthase (iNOS) complements ROS by forming reactive nitrogen species, contributing to both rapid and sustained bactericidal effects, particularly in activated macrophages.^[40] Lysosomal hydrolases, including cathepsins B, D, and L, are activated by the low pH to proteolytically degrade engulfed material, while antimicrobial peptides like defensins and cathelicidins disrupt microbial membranes.^[41] NOX2 activity also modulates proteolysis by inactivating excess cysteine cathepsins through oxidation, preventing host tissue damage.^[42] After degradation, undigested remnants or non-degradable material from the phagolysosome are managed through recycling pathways to maintain cellular homeostasis. These remnants can be packaged into exosomes derived from multivesicular bodies within the endolysosomal system and secreted extracellularly, preventing intracellular accumulation.^[43] Alternatively, autophagy pathways, including macroautophagy and LC3-associated phagocytosis, engulf persistent phagolysosomal contents for further degradation or recycling of nutrients, with shared molecular machinery like SNAREs linking these processes to lysosomal compartments.^[44]

Phagocytic Cells and Receptors

Professional Phagocytes

Professional phagocytes represent a subset of innate immune cells specialized for efficient phagocytosis as their primary function, distinguishing them from other leukocytes by their high capacity to engulf and degrade pathogens, apoptotic cells, and debris. These cells, including neutrophils, monocytes, macrophages, dendritic cells, and osteoclasts, originate from hematopoietic stem cells in the bone marrow through the myeloid lineage, specifically from common myeloid progenitors that give rise to granulocyte-monocyte progenitors and further differentiate into mature forms.^[45] Monocytes are circulating precursors to macrophages and other tissue phagocytes, exhibiting phagocytic activity in blood and upon migration to tissues. They express similar receptors to macrophages and contribute to early inflammatory responses by engulfing pathogens and debris before differentiating. Neutrophils, the most abundant circulating leukocytes in humans, are short-lived granulocytes with a lifespan of hours to days, produced at a remarkable rate of approximately 10^{11} cells per day to maintain steady-state levels and respond to infections. They exhibit high phagocytic capacity, containing azurophilic, specific, and gelatinase granules loaded with antimicrobial enzymes, reactive oxygen species-generating oxidases like NADPH oxidase, and antimicrobial peptides such as defensins, enabling rapid killing within phagosomes. Neutrophils express abundant phagocytic receptors, including Fcγ receptors for opsonized particles and complement receptors, facilitating their recruitment to sites of inflammation where they perform high-volume phagocytosis before undergoing apoptosis.^[46]^[47]^[48] Macrophages are long-lived, versatile phagocytes that reside in tissues throughout the body, originating primarily from circulating monocytes that differentiate upon extravasation, although many tissue populations self-renew from embryonic precursors seeded early in development. They express a diverse array of phagocytic receptors at high levels and possess lysosomes rich in hydrolytic enzymes and antimicrobial factors, supporting sustained phagocytic activity and antigen processing. Macrophages exhibit tissue-specific specializations; for instance, alveolar macrophages in the lungs clear inhaled particles and surfactants via surfactant protein-mediated opsonization, while microglia in the central nervous system maintain neural homeostasis by phagocytosing synaptic debris and pathogens without eliciting excessive inflammation.^[49]^[50]^[51] Osteoclasts are multinucleated cells specialized for bone resorption, functioning as professional phagocytes by engulfing and degrading bone matrix through phagocytic mechanisms similar to macrophages, from which they derive via the monocyte-macrophage lineage. They express receptors like RANK and integrins for targeted bone phagocytosis, playing a key role in skeletal remodeling.^[52] Dendritic cells, particularly conventional or myeloid dendritic cells, serve as professional phagocytes focused on sampling antigens from the environment for subsequent presentation to adaptive immune cells, deriving from bone marrow myeloid precursors that migrate to tissues as immature cells. They possess enhanced endocytic machinery and high surface expression of receptors like DEC-205 and mannose receptors, allowing efficient uptake of pathogens in peripheral tissues before maturation and migration to lymph nodes. Unlike neutrophils and macrophages, dendritic cells prioritize phagocytic antigen capture over bulk clearance, integrating phagocytosis with MHC class II loading to bridge innate and adaptive immunity.^[53]

Non-Professional Phagocytes and Receptors

Non-professional phagocytes are cells that engage in phagocytosis sporadically, primarily to maintain local tissue homeostasis rather than as a core immune function, in contrast to professional phagocytes like macrophages that perform it continuously and at high efficiency. These cells include epithelial cells, fibroblasts, and endothelial cells, which can internalize apoptotic bodies, cellular debris, or pathogens under specific physiological or pathological conditions. For instance, intestinal microfold (M) cells, a specialized subset of epithelial cells in the follicle-associated epithelium of Peyer's patches, actively sample luminal antigens through phagocytosis and transcytosis to underlying immune cells.^[54]^[55] In developmental contexts, non-professional phagocytosis supports tissue remodeling, such as in the retinal pigment epithelium where epithelial cells clear shed photoreceptor outer segments, or in the lens where epithelial cells engulf apoptotic lens fiber cells. Fibroblasts contribute to wound healing by removing local debris, while endothelial cells, particularly liver sinusoidal endothelial cells, participate in scavenging aged or damaged erythrocytes and apoptotic cells from circulation. These activities are often context-specific, triggered by local signals like inflammation, where Toll-like receptor (TLR) signaling upregulates phagocytic machinery in epithelial and other non-professional cells to enhance debris clearance during infection or injury.^[56]^[57]^[58] Distinct receptors mediate recognition in non-professional phagocytes, differing in expression and specificity from those dominant in professionals. Stabilin-1 and Stabilin-2, scavenger receptors primarily on endothelial cells, bind phosphatidylserine-exposed apoptotic cells and facilitate their engulfment, promoting anti-inflammatory outcomes like interleukin-10 production. MerTK, a receptor tyrosine kinase from the TAM family, is expressed on fibroblasts, epithelial cells, and endothelial cells, where it drives efferocytosis by integrating "eat-me" signals such as phosphatidylserine exposure, often in cooperation with integrins like αvβ5. In intestinal M cells, uptake involves glycoprotein 2 (GP2) and other pattern recognition receptors that enable transcytosis of particulate antigens without full lysosomal degradation. These receptors support targeted, lower-volume phagocytosis suited to barrier or supportive roles.^[59]^[60]^[57] Functions of non-professional phagocytes center on localized maintenance, such as clearing apoptotic cells to prevent secondary necrosis and inflammation in tissues, or transcytosing pathogens across epithelial barriers to initiate immune sampling without widespread dissemination. For example, M cells transport bacteria like Salmonella across the gut mucosa to subepithelial dendritic cells, aiding mucosal immunity while limiting epithelial damage. Unlike professional phagocytes, which handle large-scale pathogen elimination, non-professionals operate at reduced rates—often engulfing smaller particles or fewer targets per cell—and possess limited lysosomal capacity, making them less effective for high-burden clearance but essential for niche homeostasis. This auxiliary role complements professionals by providing rapid, site-specific responses in non-immune tissues.^[55]^[61]^[56]

Roles in the Immune System

Pathogen Clearance and Innate Immunity

Phagocytosis serves as a cornerstone of innate immunity by enabling professional phagocytes, such as neutrophils and macrophages, to engulf and eliminate invading pathogens through opsonin-dependent mechanisms. Opsonins like complement component C3b and antibodies coat microbial surfaces, facilitating recognition and binding to receptors on phagocytes, which promotes efficient uptake.^[62] Once internalized within phagosomes, engulfed pathogens are subjected to a respiratory burst, where the NADPH oxidase complex generates reactive oxygen species (ROS) that damage microbial components, leading to the death of the majority of bacteria.^[63] Specific pathogens are targeted via distinct receptors that enhance clearance. For instance, bacteria such as Streptococcus pneumoniae are opsonized with iC3b and phagocytosed primarily through complement receptor 3 (CR3) on macrophages and neutrophils, initiating intracellular killing.^[64] Fungi like Candida albicans in yeast form are recognized by the β-glucan receptor Dectin-1 on macrophages, triggering phagocytosis and subsequent ROS production for fungal destruction.^[65] Parasites such as Toxoplasma gondii may initially enter macrophages via phagocytosis, but virulent strains rapidly form a parasitophorous vacuole that modifies the phagosomal membrane to prevent lysosomal fusion and acidification, allowing intracellular survival.^[66] Pathogens have evolved evasion strategies to counteract phagocytic clearance. Yersinia species deploy type III secretion system effectors, such as YopE and YopH, which inhibit actin polymerization at the host cell cortex, thereby blocking phagosome formation and uptake.^[67] Similarly, Mycobacterium tuberculosis arrests phagosome maturation by secreting lipids like LAM that interfere with Rab GTPase recruitment and endosomal fusion, enabling the bacterium to replicate within immature phagosomes and avoid ROS exposure.^[68] Beyond direct killing, phagocytosis amplifies innate responses through inflammatory signaling. Engulfment of pathogens or pathogen-associated molecular patterns activates the NLRP3 inflammasome in phagocytes, leading to caspase-1 cleavage and release of proinflammatory cytokines, including IL-1β, which recruits additional immune cells to the infection site.^[69] This cytokine burst enhances pathogen clearance but can also contribute to tissue inflammation if dysregulated.^[70]

Antigen Presentation and Adaptive Immunity

Phagocytosis serves as a critical bridge between innate and adaptive immunity by enabling professional antigen-presenting cells (APCs), such as dendritic cells and macrophages, to process engulfed pathogens or debris into peptides for presentation on major histocompatibility complex (MHC) molecules. Following engulfment, phagosomes fuse with lysosomes to form phagolysosomes, where acidic hydrolases and proteases degrade the cargo into peptides of approximately 13-25 amino acids. These peptides are then loaded onto MHC class II molecules in a process facilitated by the invariant chain and HLA-DM, allowing transport to the cell surface for recognition by CD4+ T helper cells. This MHC II pathway predominantly activates helper T cells to orchestrate cytokine production, B cell activation, and further immune amplification.00761-6) A specialized mechanism known as cross-presentation enables dendritic cells to present exogenous phagocytosed antigens on MHC class I molecules to CD8+ cytotoxic T cells, bypassing the classical endogenous pathway. In this process, antigens escape lysosomal degradation and are translocated to the cytosol, where proteasomes generate shorter peptides (8-10 amino acids); these are transported into the endoplasmic reticulum (ER) via TAP transporters for loading onto MHC I, often involving phagosome-ER fusion or Sec22b-mediated vesicular transport. Dendritic cells are particularly efficient at cross-presentation due to their specialized phagosomal maturation, which balances degradation with antigen preservation, and this capability is essential for priming CD8+ T cell responses against viruses and tumors.01359-6)^[71] The outcomes of phagocytic antigen presentation include robust activation of adaptive T cell responses, but the process can also promote tolerance when engulfing self-antigens from apoptotic cells, thereby suppressing autoimmunity. Tolerogenic phagocytosis induces immunosuppressive signals, such as production of TGF-β and IL-10, leading to regulatory T cell differentiation or T cell anergy, which maintains self-tolerance and prevents inflammatory responses to harmless self-components. This dual role underscores phagocytosis's regulatory function in immune homeostasis. Efficiency of presentation is relatively low, with only a small fraction of engulfed antigens successfully processed and displayed on MHC molecules, though adjuvants like TLR ligands can enhance uptake and maturation to improve T cell priming.^[72]^[73]

Phagocytosis in Development and Homeostasis

Apoptotic Cell Engulfment

Apoptotic cell engulfment, also known as efferocytosis, is a specialized form of phagocytosis that rapidly clears dying cells to maintain tissue homeostasis and prevent inflammatory responses. This process is essential in multicellular organisms, where billions of cells undergo programmed cell death daily without eliciting autoimmunity or tissue damage. In humans, approximately 10^11 apoptotic cells are cleared each day, primarily by professional phagocytes such as macrophages and dendritic cells, as well as non-professional cells like epithelial and endothelial cells.^[74] The engulfment begins with the release of "find-me" signals from apoptotic cells to recruit phagocytes to the site of death while the plasma membrane remains intact. These soluble signals include lysophosphatidylcholine (LPC), generated by the enzymatic activity of caspase-3-activated calcium-independent phospholipase A2, which attracts phagocytes via G-protein-coupled receptors like G2A. Other find-me signals encompass nucleotides such as ATP and UTP, released through pannexin-1 channels, which bind to purinergic receptors (e.g., P2Y2) on phagocytes to promote migration and cytoskeletal rearrangements. Once in proximity, apoptotic cells expose "eat-me" signals, most prominently phosphatidylserine (PS), which is externalized from the inner plasma membrane leaflet to the outer surface through the action of phospholipid scramblases like TMEM16F, activated downstream of caspase signaling. This PS exposure is a conserved hallmark that distinguishes apoptotic cells from healthy ones.^[75]^[76]^[77] Recognition of these eat-me signals occurs via a diverse array of phagocyte receptors, often requiring bridging molecules to connect PS on the apoptotic cell to the phagocyte surface. Direct receptors include brain-specific angiogenesis inhibitor 1 (BAI1), which binds PS through its thrombospondin repeats to activate Rac1 GTPase for cytoskeletal protrusion, and stabilins (Stab1 and Stab2), which recognize PS and oxidized phospholipids to facilitate engulfment in vascular and lymphatic tissues. The TAM family of receptor tyrosine kinases—Tyro3, Axl, and MerTK—plays a central role, particularly MerTK, which engages PS via bridging proteins such as growth arrest-specific gene 6 (Gas6) or protein S, leading to downstream signaling that promotes pseudopod extension and particle internalization. These receptors collectively ensure efficient uptake without inflammation.^[78]^[79] Upon engulfment, the apoptotic cargo is processed in a manner that suppresses pro-inflammatory responses and promotes resolution. Phagocytes release anti-inflammatory cytokines such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), which inhibit NF-κB activation and dampen TNF-α and IL-1β production, thereby preventing secondary necrosis and autoantigen exposure. Additionally, efferocytosis enables the recycling of nucleotides and other cellular components from engulfed cells, supporting de novo purine synthesis in phagocytes and contributing to tissue repair processes. Defects in this clearance mechanism, such as impaired MerTK function or reduced PS recognition, lead to accumulation of apoptotic debris, triggering autoimmunity resembling systemic lupus erythematosus (SLE), characterized by autoantibodies against nuclear antigens and chronic inflammation.^[80]^[79]^[81]

Tissue Repair and Remodeling

Phagocytosis plays a crucial role in tissue repair and remodeling by enabling the clearance of non-apoptotic cellular debris and extracellular matrix (ECM) components following injury or during developmental processes. In wound healing, macrophages actively phagocytose necrotic debris and damaged tissue fragments to prevent secondary inflammation and facilitate regeneration.^[82] Similarly, during embryogenesis, microglial cells in the brain prune excess synapses through phagocytic engulfment, refining neural circuits essential for proper development.^[83] In atherosclerosis, efferocytosis by macrophages removes foam cells laden with oxidized lipids, maintaining plaque stability and limiting lesion progression.^[84] Mechanistically, phagocytosis of ECM fragments is often mediated by integrins, such as α3β1, which bind denatured collagen and facilitate uptake by fibroblasts and macrophages, promoting matrix remodeling without triggering excessive inflammation.^[85] This process is enhanced in alternatively activated M2-polarized macrophages, which arise in response to IL-4 and IL-13 signals during the repair phase, shifting from pro-inflammatory M1 states to support tissue homeostasis through efficient debris clearance and secretion of growth factors.^[82] Successful phagocytosis in these contexts yields anti-inflammatory outcomes, including the release of vascular endothelial growth factor (VEGF) by macrophages following engulfment of debris, which stimulates angiogenesis to restore vascular integrity in healing wounds.^[86] It also resolves inflammation by suppressing pro-fibrotic cytokines like TGF-β. Defects in phagocytic clearance, however, impair these protective effects; for instance, reduced uptake of apoptotic or necrotic cells diminishes prostaglandin E2 production, leading to unchecked TGF-β activation and progressive fibrosis in tissues such as the lung.^[87] An illustrative example occurs in Drosophila oogenesis, where border cells migrate collectively to the oocyte; phagocytosis genes like draper and ced-12 nonautonomously promote this migration by enabling the clearance of obstructive cellular remnants, ensuring precise pathfinding and tissue organization.^[88]

Phagocytosis Across Organisms

In Protists and Unicellular Eukaryotes

In protists and unicellular eukaryotes, phagocytosis primarily serves as a constitutive feeding mechanism essential for nutrient acquisition and survival, distinct from its immune-related roles in multicellular organisms.^[89] These organisms engulf particulate matter such as bacteria, algae, and other microbes through specialized structures, forming phagosomes that fuse with lysosome-like compartments to create digestive vacuoles analogous to phagolysosomes, where hydrolytic enzymes break down ingested material.^[90] This process enables protists to thrive in diverse aquatic and soil environments by converting solid particles into soluble nutrients for energy and growth. Amoebae exemplify phagocytosis via pseudopodial extension for prey capture. In Entamoeba histolytica, a parasitic amoeba, phagocytosis involves adherence to bacterial surfaces via lectins, followed by pseudopod formation to engulf prey, supporting both nutritional needs and virulence by allowing tissue invasion and dysbiosis in the host gut.^[91] This feed-forward regulation enhances parasite proliferation, as phagocytosed bacteria provide essential nutrients while contributing to pathogenic inflammation.^[92] Similarly, free-living amoebae like Amoeba proteus use dynamic pseudopodia to surround and internalize bacteria or yeast, with digestive vacuoles acidifying to pH 4-5 for efficient proteolysis.^[93] Ciliates such as Paramecium employ an oral groove lined with cilia to channel food particles toward the cytostome, initiating phagocytosis.^[94] Beating cilia create currents that direct bacteria or algae into the gullet, where a food vacuole pinches off and circulates through the cytoplasm, fusing with acidosomes to form a phagolysosome-like structure for digestion.^[95] This ciliary mechanism allows rapid ingestion rates, up to 26,000 particles per hour, optimizing nutrient uptake in planktonic environments.^[96] Dinoflagellates often exhibit mixotrophic lifestyles, combining photosynthesis with phagotrophic feeding. Heterotrophic species like Oxyrrhis marina generate feeding currents via flagella to intercept prey, engulfing bacteria, nanoflagellates, or diatoms directly at a transient cytostome through membrane invagination.^[97] In mixotrophs such as Pfiesteria piscicida, phagocytosis supplements autotrophy by capturing picoeukaryotes, with peduncle-like structures aiding capture in some cases, though direct engulfment predominates for smaller particles.^[98] These adaptations enable dinoflagellates to exploit nutrient-poor oceanic niches.^[99] Phagotrophic protists play a pivotal ecological role in microbial loops, acting as primary grazers of bacteria and phytoplankton to recycle nutrients in aquatic ecosystems.^[100] By phagocytosing up to 100% of bacterial production daily in plankton communities, they release dissolved organic matter and inorganic nutrients, sustaining higher trophic levels and preventing nutrient limitation in oceans and freshwater systems.^[101] In pathogenic contexts, phagocytosis-like processes facilitate host cell invasion. For instance, Plasmodium falciparum merozoites invade erythrocytes through apical attachment, inducing membrane invagination that envelops the parasite, mimicking phagocytic engulfment to establish intracellular residence without immediate digestion.^[102] This mechanism, involving actin remodeling and tight junction formation, underscores how unicellular parasites co-opt phagocytic elements for survival and replication.^[103]

Evolutionary and Comparative Aspects

Phagocytosis is believed to have ancient origins predating the eukaryotic cell, emerging from primitive engulfment processes that facilitated symbiotic relationships between prokaryotes, such as the uptake of an alphaproteobacterium that evolved into the mitochondrion during eukaryogenesis.^[104] This capability likely arose through early predatory interactions, where one prokaryote engulfed another without immediate digestion, setting the stage for endosymbiosis.^[89] In modern eukaryotes, the core machinery for phagocytosis, including actin cytoskeleton remodeling via the Arp2/3 complex for branched filament formation, is highly conserved across metazoans, underscoring its fundamental role in cellular evolution.^[105] While true phagocytosis—defined as the engulfment of large particles (>0.5 μm) into a vesicle—is absent in plants due to rigid cell walls, analogous endocytic processes enable selective uptake of extracellular materials, such as in root hair cells where clathrin-mediated endocytosis facilitates nutrient acquisition and signaling.^[106] In fungi, phagocytosis is limited and primarily observed in unicellular forms like yeasts, but multicellular species rely on hyphal extensions for extracellular enzymatic digestion and nutrient absorption across substrates, representing a divergent strategy for resource capture adapted to their saprotrophic or pathogenic lifestyles.^[107] Comparatively, phagocytosis in invertebrates, such as insect hemocytes, mirrors the innate recognition and engulfment functions of vertebrate macrophages and neutrophils, with hemocytes employing pattern recognition receptors to clear pathogens without adaptive immunity integration.^[108] In vertebrates, this process has evolved to bridge innate and adaptive responses, where phagocytes process antigens for presentation to T cells, enhancing immunological memory.^[109] Pathogens like viruses have co-evolved countermeasures, including mimicry of apoptotic or "eat-me" signals on host cells to subvert phagocytosis and promote viral spread or persistence.^[110] Recent advances in single-cell genomics have illuminated the deep evolutionary roots of phagocytosis, revealing orthologs of key genes involved in actin dynamics and particle recognition in choanoflagellates, the unicellular precursors to animals, indicating that phagocytic competence predates multicellularity.^[111] These findings, combined with protist studies showing phagocytosis as a primary feeding mode, highlight a continuum of this trait across eukaryotic diversity, with divergences driven by ecological niches and organismal complexity.^[112]

History and Recent Advances

Discovery and Historical Milestones

The concept of phagocytosis emerged from early microscopic observations of cellular movement and engulfment in the mid-19th century. In 1863, German pathologist Friedrich Daniel von Recklinghausen described the contractility and amoeboid mobility of pus cells during acute inflammation, providing the first detailed account of leukocyte pseudopodia extension and retraction, which foreshadowed the active process of particle ingestion by cells.^[113] A major breakthrough occurred in the 1880s through the work of Russian zoologist Élie Metchnikoff, who systematically studied phagocytic cells in transparent starfish larvae. In 1882, Metchnikoff inserted rose thorns into the larvae and observed that motile mesodermal cells rapidly migrated to and engulfed the intruders, demonstrating phagocytosis as a protective mechanism against foreign material. He extended these findings to vertebrates, proposing that phagocytes—such as macrophages and leukocytes—form the foundation of innate immunity by actively destroying pathogens, a view that challenged the dominant humoral theory of immunity, which emphasized soluble factors in blood serum as the primary defense, as advocated by contemporaries like Paul Ehrlich. Metchnikoff's phagocytosis theory, emphasizing cellular engagement over passive humoral responses, revolutionized immunology and earned him the 1908 Nobel Prize in Physiology or Medicine, shared with Ehrlich for their complementary insights into immunity.^[114]^[115]^[116] Subsequent key experiments in the early 20th century clarified the mechanisms enhancing phagocytic efficiency. In 1903, British bacteriologists Almroth Wright and Stewart Douglas identified opsonins—serum proteins, including antibodies and complement components—that coat bacteria, markedly increasing their uptake by phagocytes through improved recognition and attachment. This discovery, demonstrated via in vitro assays measuring bacterial ingestion by human leukocytes, underscored the interplay between humoral factors and cellular activity in immunity.^[117]^[118] Advances in imaging technology further illuminated the intracellular dynamics of phagocytosis. The development of electron microscopy in the 1930s enabled higher-resolution visualization, with initial studies in the 1940s and 1950s revealing the formation of phagosomes—membrane-bound vesicles enclosing engulfed particles—within leukocytes and macrophages. For instance, early electron micrographs from the 1950s depicted the sequestration of bacteria in these vacuoles, highlighting the structural basis for intracellular digestion.^[2] By the mid-20th century, research shifted toward identifying specific receptors mediating phagocytosis. In the 1950s, immunologist Stephen V. Boyden's studies on antibody adsorption to spleen cells and leukocytes demonstrated how immune complexes bind to phagocyte surfaces, facilitating opsonin-dependent engulfment and linking humoral opsonization to cellular responses. This work built on earlier opsonin concepts and utilized novel in vitro assays to quantify phagocytic enhancement.^[119] A pivotal milestone in the 1970s was the identification and characterization of Fc receptors on phagocytes, which bind the Fc portion of IgG antibodies coating targets. Seminal studies, such as those isolating Fcγ receptors from macrophages, revealed their role in triggering actin reorganization and particle internalization, explaining antibody-dependent phagocytosis and shifting the paradigm from nonspecific cellular immunity to receptor-mediated specificity.^[120]^[12]

Contemporary Research and Therapeutic Implications

Recent research has illuminated the role of transient receptor potential (TRP) channels, particularly TRPM7, in regulating phagosome acidification during efferocytosis in macrophages. Studies from 2022 to 2024 have shown that TRPM7 facilitates calcium influx necessary for phagosomal maturation and pH lowering, with its inhibition impairing the clearance of apoptotic cells. A 2024 review highlights TRPM7's broader involvement in endosomal pH dynamics, suggesting potential therapeutic modulation to enhance phagocytic efficiency in inflammatory diseases.^[121]^[122]^[122] Advancements in understanding metabolic processes post-phagocytosis reveal that macrophages recycle components from engulfed bacteria to support their own immunometabolism. A 2025 Nature study demonstrates that phagocytosed dead bacteria enrich cells with cAMP, which sustains the AMP pool to activate AMPK, fueling macrophage survival and reducing reactive oxygen species production, thereby skewing responses toward persistence rather than hyperinflammation. This recycling mechanism, observed in both in vitro and murine models, underscores how pathogens inadvertently bolster host cell resilience.^[123]^[123] Mechanical properties of targets also influence phagocytic uptake, as evidenced by 2025 research on neutrophil interactions with elastic particles. In Science Advances, deformable hydrogel particles mimicking soft pathogens were phagocytosed more efficiently by human neutrophils than rigid ones, regardless of modulus, challenging prior models and informing vascular-targeted drug carrier designs. This elasticity-dependent enhancement promotes faster engulfment and could optimize nanoparticle therapies for infection control.^[124]^[124] Therapeutic strategies increasingly target "don't eat me" signals to boost phagocytosis in cancer. Anti-CD47 antibodies block the CD47-SIRPα interaction, promoting macrophage-mediated tumor cell clearance; phase II trials from 2023-2025 report improved outcomes in hematologic malignancies when combined with checkpoint inhibitors.^[125] Enhancing efferocytosis addresses atherosclerosis by clearing apoptotic cells to stabilize plaques; a 2025 study using macrophage-biomimetic nanoparticles synergistically promoted both efferocytosis and cholesterol efflux in ApoE−/− mice, reducing lesion progression. Nanoparticle designs mimicking opsonins, such as phosphatidylserine-coated liposomes, facilitate targeted drug delivery by exploiting phagocytic pathways; 2024 research shows these enhance macrophage uptake.^[126]^[127] In neurodegeneration, phagocytosis aids amyloid-β (Aβ) clearance, with emerging therapies focusing on microglial activation. A 2022 study emphasizes SYK signaling in coordinating Aβ compaction and engulfment by microglia, reducing plaque burden in Alzheimer's models. Fungal pathogens evade phagocytosis through cell wall modifications and immune modulation, informing antimicrobial development; 2023-2025 reviews detail how Candida albicans cleaves host peptides to inhibit recognition, prompting strategies like β-glucan adjuvants to restore uptake. Trained immunity via β-glucan priming enhances phagocytic responses; a 2025 trial showed a single dose increased macrophage antigen presentation and antibody production, bolstering long-term defense against infections.^[128]^[129]^[130] Challenges persist in overcoming pathogen resistance, such as Mycobacterium tuberculosis (Mtb) modulation of phagosome maturation to evade killing. Recent 2023-2025 analyses reveal Mtb effectors like ESX-1 that arrest phagolysosome fusion, sustaining intracellular survival; targeting these via efflux pump inhibitors shows promise in preclinical models. Ethical concerns surround gene-edited phagocytes, including CRISPR-modified macrophages for enhanced function; 2023-2025 discussions highlight risks of off-target effects, germline transmission, and equitable access, urging stringent oversight to balance therapeutic potential against unintended ecological or societal impacts.^[131]^[132]^[133]^[133]

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Feb 26, 2025 · In this study, we show that ingested bacteria constitute an alternative nutrient source that skews immunometabolic host responses.
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Tumor associated macrophages as key contributors and targets in ...
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Synergistic enhancement of efferocytosis and cholesterol efflux via ...
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New antifungal strategies and drug development against WHO ...
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