title: CD11b/CD18 (Mac-1) is a novel surface receptor for extracellular double-stranded RNA to mediate cellular inflammatory responses.
abstract: During viral infection, extracellular dsRNA is a potent signaling molecule that activates many innate immune cells, including macrophages. TLR3 is a well-known receptor for extracellular dsRNA, and internalization of extracellular dsRNA is required for endosomal TLR3 activation. Preserved inflammatory responses of TLR3-deficient macrophages to extracellular dsRNA strongly support a TLR3-independent mechanism in dsRNA-mediated immune responses. The present study demonstrated that CD11b/CD18 (Mac-1 [macrophage-1 Ag]), a surface integrin receptor, recognized extracellular dsRNA and induced macrophage immune responses. CD11b deficiency reduced inflammatory cytokine induction elicited by polyinosinic:polycytidylic acid (poly I:C; a synthetic dsRNA) in mouse sera and livers, as well as in cultured peritoneal macrophages. dsRNA-binding assay and confocal immunofluorescence showed that Mac-1, especially the CD11b subunit, interacted and colocalized with poly I:C on the surface of macrophages. Further mechanistic studies revealed two distinct signaling events following dsRNA recognition by Mac-1. First, Mac-1 facilitated poly I:C internalization through the activation of PI3K signaling and enhanced TLR3-dependent activation of IRF3 in macrophages. Second, poly I:C induced activation of phagocyte NADPH oxidase in a TLR3-independent, but Mac-1-dependent, manner. Subsequently, phagocyte NADPH oxidase-derived intracellular reactive oxygen species activated MAPK and NF-κB pathways. Our results indicate that extracellular dsRNA activates Mac-1 to enhance TLR3-dependent signaling and to trigger TLR3-independent, but Mac-1-dependent, inflammatory oxidative signaling, identifying a novel mechanistic basis for macrophages to recognize extracellular dsRNA to regulate innate immune responses. This study identifies Mac-1 as a novel surface receptor for extracellular dsRNA and implicates it as a potential therapeutic target for virus-related inflammatory diseases.
authors.affiliation: Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.forename: Jieying
authors.initials: J
authors.lastname: Liao
authors.forename: Jim
authors.initials: J
authors.lastname: Aloor
authors.forename: Hui
authors.initials: H
authors.lastname: Nie
authors.forename: Belinda C
authors.initials: BC
authors.lastname: Wilson
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fessler
authors.forename: Hui-Ming
authors.initials: HM
authors.lastname: Gao
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism*; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005110:Extracellular Space / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051196:Toll-Like Receptor 3
chemical_list: D039481:CD11b Antigen; D018821:CD18 Antigens; D018836:Inflammation Mediators; D016177:Macrophage-1 Antigen; D012330:RNA, Double-Stranded; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D019255:NADPH Oxidases