Abstract
Phagocytosis is a specialized process that enables cellular ingestion and clearance of microbes, dead cells and tissue debris that are too large for other endocytic routes. As such, it is an essential component of tissue homeostasis and the innate immune response, and also provides a link to the adaptive immune response. However, ingestion of large particulate materials represents a monumental task for phagocytic cells. It requires profound reorganization of the cell morphology around the target in a controlled manner, which is limited by biophysical constraints. Experimental and theoretical studies have identified critical aspects associated with the interconnected biophysical properties of the receptors, the membrane, and the actin cytoskeleton that can determine the success of large particle internalization. In this review, we will discuss the major physical constraints involved in the formation of a phagosome. Focusing on two of the most-studied types of phagocytic receptors, the Fcγ receptors and the complement receptor 3 (αMβ2 integrin), we will describe the complex molecular mechanisms employed by phagocytes to overcome these physical constraints.
Highlights
Internalization of large particulate material by phagocytosis is a fundamental and well-conserved cellular mechanism of eukaryotic organisms
The observation that short antigens induce higher tyrosine phosphorylation of Fc γ receptors (FcγR) and particle internalization than longer antigens, independent of receptor density, confirms the notion that steric constraints can regulate receptor signaling [64]. These findings suggest that the mechanism of CD45 exclusion induced by liquid-liquid phase separation of signaling clusters, as shown for the T cell receptor in a reconstituted system, might not be sufficient to segregate CD45 and FcγRs in macrophages [66]
Since phagocytosis is a cellular process broadly employed across eukaryotes, it seems likely that phagocytes employ fundamentally shared molecular mechanisms to overcome the physical constraints imposed by the internalization of large particulate material by cells
Summary
Internalization of large particulate material by phagocytosis is a fundamental and well-conserved cellular mechanism of eukaryotic organisms. One model suggests that in the absence of actin polymerization to drive protrusion of the phagocytic cup, a passive zipper based on receptor diffusion and random membrane fluctuations could be sufficient to mediate internalization of small particles [30]. While internalization is possible through receptor binding solely driven by passive diffusion and random membrane fluctuations, this remains slow and highly inefficient for large particles, unless work is produced to promote cell surface deformation [30] Consistent with this notion, multiple models suggest that a protrusive force is required to deform the cell around the target particle to initiate formation of the phagocytic cup [11, 29, 72]. Vinculin can be recruited to reinforce the talin molecular clutch in myosin II dependent and independent manners
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