title: Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells.
abstract: The recognition and clearance of dead cells is a process that must occur efficiently to prevent an autoimmune or inflammatory response. Recently, a process was identified wherein the autophagy machinery is recruited to pathogen-containing phagosomes, termed MAPLC3A (LC3)-associated phagocytosis (LAP), which results in optimal degradation of the phagocytosed cargo. Here, we describe the engagement of LAP upon uptake of apoptotic, necrotic, and RIPK3-dependent necrotic cells by macrophages. This process is dependent on some members of the classical autophagy pathway, including Beclin1, ATG5, and ATG7. In contrast, ULK1, despite being required for autophagy, is dispensable for LAP induced by uptake of microbes or dead cells. LAP is required for efficient degradation of the engulfed corpse, and in the absence of LAP, engulfment of dead cells results in increased production of proinflammatory cytokines and decreased production of anti-inflammatory cytokines. LAP is triggered by engagement of the TIM4 receptor by either phosphatidylserine (PtdSer)-displaying dead cells or PtdSer-containing liposomes. Therefore, the consequence of phagocytosis of dead cells is strongly affected by those components of the autophagy pathway involved in LAP.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martinez
authors.forename: Johann
authors.initials: J
authors.lastname: Almendinger
authors.forename: Andrew
authors.initials: A
authors.lastname: Oberst
authors.forename: Rachel
authors.initials: R
authors.lastname: Ness
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Dillon
authors.forename: Patrick
authors.initials: P
authors.lastname: Fitzgerald
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hengartner
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
mesh_terms: D000818:Animals; D001343:Autophagy / Q000276:immunology; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D017173:Caenorhabditis elegans / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D009336:Necrosis / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology*; D010588:Phagosomes / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
chemical_list: C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D016207:Cytokines; D018836:Inflammation Mediators; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C498708:Ptdsr protein, mouse; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D000071193:Autophagy-Related Protein 7