title: Extracellular stimulation of VSIG4/complement receptor Ig suppresses intracellular bacterial infection by inducing autophagy.
abstract: VSIG4/CRIg (V-set and immunoglobulin domain containing 4) is a transmembrane receptor of the immunoglobulin superfamily that is expressed specifically on macrophages and mature dendritic cells. VSIG4 signaling accelerates phagocytosis of C3-opsonized bacteria, thereby efficiently clearing pathogens within macrophages. We found that VSIG4 signaling triggered by C3-opsonized Listeria (opLM) or by agonistic anti-VSIG4 monoclonal antibody (mAb) induced macrophages to form autophagosomes. VSIG4-induced autophagosomes were selectively colocalized with the intracellular LM while starvation-induced autophagosomes were not. Consistent with these results, the frequency of autophagosomes induced by infection with opLM was lower in VSIG4-deficient bone marrow-derived macrophages (BMDMs) than in WT BMDMs. Furthermore, when VSIG4 molecules were overexpressed in HeLa cells, which are non-macrophage cells, VSIG4 triggering led to efficient uptake of LM, autophagosome formation, and killing of the infected LM. These findings suggest that VSIG4 signaling not only promotes rapid phagocytosis and killing of C3-opsonized intracellular bacteria, as previously reported, but also induces autophagosome formation, eliminating the LM that have escaped from phagosomes. We conclude that VSIG4 signaling provides an anti-immune evasion mechanism that prevents the outgrowth of intracellular bacteria in macrophages.
authors.affiliation: a Eutilex , The Catholic University School of Medicine Seoul , Korea.
authors.forename: Kwang H
authors.initials: KH
authors.lastname: Kim
authors.affiliation: b Cancer Immunology Branch , Division of Cancer Biology, National Cancer Center , Goyang , Korea.
authors.forename: Beom K
authors.initials: BK
authors.lastname: Choi
authors.affiliation: c Immune Cell Production Unit , Program for Immunotherapeutic Research, National Cancer Center , Goyang , Korea.
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.affiliation: b Cancer Immunology Branch , Division of Cancer Biology, National Cancer Center , Goyang , Korea.
authors.forename: Chungyong
authors.initials: C
authors.lastname: Han
authors.affiliation: b Cancer Immunology Branch , Division of Cancer Biology, National Cancer Center , Goyang , Korea.
authors.forename: Ho S
authors.initials: HS
authors.lastname: Oh
authors.affiliation: b Cancer Immunology Branch , Division of Cancer Biology, National Cancer Center , Goyang , Korea.
authors.forename: Don G
authors.initials: DG
authors.lastname: Lee
authors.affiliation: a Eutilex , The Catholic University School of Medicine Seoul , Korea.|b Cancer Immunology Branch , Division of Cancer Biology, National Cancer Center , Goyang , Korea.|d Department of Medicine , Tulane University Health Sciences Center , New Orleans , LA , USA.
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000071182:Autophagosomes / Q000378:metabolism; D001343:Autophagy; D000071187:Autophagy-Related Protein 5 / Q000235:genetics; D001424:Bacterial Infections / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008087:Listeria / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000276:immunology; D010588:Phagosomes / Q000378:metabolism; D011951:Receptors, Complement / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D007074:Immunoglobulin G; D011951:Receptors, Complement; C414427:VSIG4 protein, human; C509992:VSIG4 protein, mouse
keywords: CRIg; LC3B; Listeria; VSIG4; autophagy; macrophage; ubiquitin