Cooperation among phagocytic receptors. DOI:10.3389/fimmu.2020.01066
Phagocytosis is a critical cellular process in which cells engulf and eliminate particles larger than 0.5 μm in diameter, including microorganisms, apoptotic cells, and foreign substances. This process is integral to tissue homeostasis, immune defense, and the maintenance of cellular environments. While many cell types are capable of phagocytosis, only certain specialized cells, called professional phagocytes, perform it efficiently.
Professional phagocytes include macrophages, neutrophils, monocytes, dendritic cells, and osteoclasts. These cells express unique phagocytic receptors that activate signaling pathways, facilitating particle detection, internalization, and degradation. Non-professional phagocytes, such as fibroblasts and epithelial cells, contribute to tissue maintenance by clearing dead cells, but lack the capacity to ingest microorganisms. Below, we delve into the phases of phagocytosis, the receptors involved, and its implications for health and disease.
Phases of Phagocytosis
1. Detection of the Target Particle
Professional phagocytes detect target particles using a variety of surface receptors. These include:
Non-opsonic receptors, which directly recognize pathogen-associated molecular patterns (PAMPs) on microorganisms. Examples include C-type lectins like Dectin-1 and DC-SIGN.
Opsonic receptors, which recognize host-derived proteins, such as antibodies or complement components, bound to the particle. These proteins, called opsonins, act as labels signaling the particle for phagocytosis. Fc receptors (FcRs) and complement receptors (CRs) are key opsonic receptors.
2. Activation of Internalization
Once the particle is detected, receptor-mediated signaling initiates internalization. This involves actin cytoskeleton remodeling and plasma membrane extension to enclose the particle, forming a structure known as the phagocytic cup. The cup seals to create a vesicle, the phagosome, containing the particle.
3. Phagosome Maturation
The phagosome undergoes fusion with endocytic vesicles to become a phagolysosome, a degradative organelle. This transformation involves:
Fusion with early endosomes, mediated by the GTPase Rab5.
Acquisition of Rab7 and lysosomal-associated membrane proteins (LAMPs), marking the late phagosome stage.
Acidification and enzyme enrichment in the phagolysosome, enabling degradation of the particle through reactive oxygen species (ROS) and hydrolytic enzymes.
Phagocytic Receptors and Their Roles
Non-opsonic Receptors: These receptors directly bind PAMPs, enabling phagocytes to recognize and internalize pathogens without opsonins. Examples include:
Dectin-1: Recognizes fungal β-glucans.
Mincle: Binds trehalose dimycolate from mycobacterial cell walls.
Scavenger receptors: Detect microbial lipopolysaccharides and other ligands.
Opsonic Receptors: These receptors enhance phagocytosis by binding particles labeled with opsonins such as antibodies or complement.
Fc receptors (FcRs): Engage IgG or IgA antibodies to mediate antibody-dependent phagocytosis. Fcγ receptors, such as FcγRI, FcγRII, and FcγRIII, play prominent roles in recognizing immune complexes.
Complement receptors (CRs): Detect complement components like iC3b, promoting the ingestion of complement-opsonized particles.
Efficient phagocytosis relies on signaling pathways. For Fc receptors, crosslinking by antibodies triggers activation of Src-family kinases, such as Lyn and Syk. These kinases phosphorylate receptor domains, recruiting downstream signaling proteins. Key pathways include:
Activation of PI3K and production of PIP3, which promotes actin remodeling.
Engagement of PLCγ, generating signals that mobilize calcium and activate protein kinase C (PKC).
Recruitment of the Arp2/3 complex, which nucleates actin polymerization to extend the phagocytic cup.
For complement receptors, activation of the small GTPase Rho governs actin and microtubule dynamics, leading to distinct particle "sinking" mechanisms compared to Fc receptor-mediated processes.
Phagocytosis of Apoptotic Cells
Eliminating apoptotic cells helps to prevent autoimmunity and maintain tissue health. Phagocytes detect apoptotic cells using receptors that bind to specific "eat me" signals, such as phosphatidylserine (PS), which appears on the surface of dying cells.
TIM-4, BAI-1, and stabilin-2 are key receptors for apoptotic cell clearance.
PS-binding proteins, such as lactadherin, act as intermediaries, linking apoptotic cells to integrins like αvβ3 for ingestion.
Phagocytosis and Immunological Implications
For therapeutic applications, understanding the molecular basis of phagocytosis offers opportunities to modulate immune responses, such as enhancing macrophage activity in infections or limiting overactive phagocytosis in inflammatory diseases. Emerging research into engineered opsonins and receptor-targeted drugs holds promise for future treatments.
References:
Rosales, C. (2020). Phagocytosis: Our Current Understanding of a Universal Biological Process. Frontiers in Immunology, 11, 531655. https://doi.org/10.3389/fimmu.2020.01066
