molecular basis of phagocytosis

doi:10.1006/smim.2001.0329, available online at http://www.idealibrary.com onseminars in IMMUNOLOGY, Vol. 13, 2001: pp. 337–338

Molecular basis of phagocytosis

Philippe Chavrier

Introduction

Phagocytosis, a term coined by Metchnikoff overa century ago, is defined as the ingestion of largeparticles (>0.5 µm) and microorganisms in anactin-based, evolutionarily conserved mechanism.In lower unicellular organisms it is associatedwith food uptake, while in metazoa, phagocytosiscontributes to tissue homeostasis and remodelling.Phagocytosis is also critical to host defence byallowing for the uptake and degradation of infectiousagents, and by participating in the immune andinflammatory response. The phagocytic processcomprises several sequential and complex eventsinitiated by the recognition of ligands on the surfaceof the particles by specific receptors on the surface ofthe phagocytic cells. In metazoa many cell types havemaintained some phagocytic capacity (a heritagefrom ancient single-celled amoebae?). Professionalphagocytosis, however, is the prerogative of selectedcells, monocytes/macrophages, dendritic cells, andneutrophils, that express a diversity of dedicatedphagocytic receptors. Receptor clustering at theattachment site generates a phagocytic signal that inturn leads to local polymerization of actin filamentsand to particle internalization. However, dependingon the particles and receptors involved, it appearsthat the structures and mechanisms associated withparticle ingestion are diverse, and the molecularbasis underlying this diversity is only beginning to beunravelled.

Among the best-characterized phagocyticreceptors are opsonic receptors, including Fcγreceptors (FcγRs) and complement receptors (CRs).In this issue, Cox and Greenberg review the early

From the Laboratoire de la Dynamique de la Membrane et duCytosquelette, Centre National de la recherche Scientifique UMR144,Institut Curie, 26 rue d’Ulm, 75241 Paris Cedex 5, France.E-mail: Philippe.Chavrier@curie.fr

c©2000 Academic Press1044–5323/01/060337+ 02/$35.00/0

signalling events that are triggered upon FcγR ag-gregation. FcγRs, which signal via immunoreceptortyrosine-based activation motifs (ITAMs), triggerthe focal accumulation of a diversity of signallingenzymes and adaptors leading to actin polymerizationand membrane remodelling during phagocytosis.Evidence is also presented that phosphatases (bothprotein–tyrosine and lipid phosphatases) may exertan opposite negative control over phagocytic andinflammatory responses.

In the case of FcR-mediated phagocytosis, it hasbeen anticipated that localized actin polymerizationcould provide a physical force from within the cellto drive pseudopod extension with concomitantzippering of the forming pseudopods around theopsonized particle. During the past few years,important advances have been made in the study ofhow cell-surface receptors signal to actin polymer-ization. Activation of small GTP-binding proteinsof the Rho family alters the organization of theactin cytoskeleton by turning on signalling pathwaysthat initiate actin polymerization. Castellano et al.describe distinct functions for different membersof the Rho-family of small GTP-binding proteinsin FcR- and CR-mediated phagocytosis that mayreflect the different morphology of actin assemblyat CR-mediated phagosomes as compared withFcR-mediated phagocytosis. In addition, they discussa link between the activation of Rho proteins andthe de novo nucleation and cross-linking of actinfilaments involving the haematopoietic-specificWiskott–Aldrich syndrome protein (WASP) andthe Arp2/3 complex, a complex of seven proteinsincluding the actin-related proteins Arp2 and Arp3.

It has long been known that macrophages can inter-nalize over 50% of their surface area during phagocy-tosis and some compensatory mechanisms have beenanticipated. Grinstein and colleagues review recentevidence that focal exocytosis is involved along withactin polymerization to support pseudopodial elonga-tion. The source of membranes delivered to the sitesof ingestion derives from a subcompartment of the

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endocytic pathway specialized in recycling of mem-brane to the plasmalemma. Although the machineryinvolved in focal delivery of endomembrane has yetto be identified, it appears that members of the Raband ARF families of small GTP-binding proteins alongwith localized production of phosphoinositides (PIP2and PIP3) play an essential role in this process.

In addition to its function as a barrier againstinfectious agents, phagocytosis has an essential role intissue homeostasis by removing cell corpses generatedby apoptosis. As reviewed by Fadok and Chiminiin this issue, several different types of receptorshave been discovered that recognize ‘eat me’ signalsexposed at the surface of dying cells. Althoughthe identity of these signals remains elusive, theprofound modifications of the membrane of thedying cell, including phosphatidylserine exposure,play a major role in the recognition of apoptotic cells.Signalling downstream of surface receptors involvedin the recognition of apoptotic preys has been mostlyexplored in the model organism Caenorhabditis eleganswhere two major pathways are at work. Recent dataindicate that one pathway leading to the activationof Rac (CED10 in C. elegans) may be evolutionarilyconserved in mammalian systems.

The essential role of phagocytosis in the defenceof higher organisms against infection goes farbeyond capture, and involves destruction andprocessing of microbial antigens to forms thatgenerate immune responses. As extensively reviewedby Watts and Amigorena, antigens derived fromphagocytosed material follow not only the classicalMHC class II route for antigen presentation ofexogenous antigens, but can also be presented byclass I MHC molecules under some circumstancesin a process called ‘cross-priming’. Evidence is alsoreviewed for a major contribution of dendritic cellsin these phenomena.

Microbiologists, and more recently cell biologists,have been confronted by the many differentways pathogens adversely exploit normal hostcell processes to their own profit i.e. survival andmultiplication, and phagocytosis is no exception.Here, P. Sansonetti reviews the different strategiesused by three model pathogens, Yersinia, Shigella,and Salmonella to invade professional, but also non-professional, phagocytic cells. This issue of Seminarsin Immunology provides an overview of this excitingfield and discusses the questions remaining to beaddressed by future studies.

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