title: Activation of C3a receptor is required in cigarette smoke-mediated emphysema.
abstract: Exposure to cigarette smoke can initiate sterile inflammatory responses in the lung and activate myeloid dendritic cells (mDCs) that induce differentiation of T helper type 1 (Th1) and Th17 cells in the emphysematous lungs. Consumption of complement proteins increases in acute inflammation, but the contribution of complement protein 3 (C3) to chronic cigarette smoke-induced immune responses in the lung is not clear. Here, we show that following chronic exposure to cigarette smoke, C3-deficient (C3(-/-)) mice develop less emphysema and have fewer CD11b(+)CD11c(+) mDCs infiltrating the lungs as compared with wild-type mice. Proteolytic cleavage of C3 by neutrophil elastase releases C3a, which in turn increases the expression of its receptor (C3aR) on lung mDCs. Mice deficient in the C3aR (C3ar(-/-)) partially phenocopy the attenuated responses to chronic smoke observed in C3(-/-) mice. Consistent with a role for C3 in emphysema, C3 and its active fragments are deposited on the lung tissue of smokers with emphysema, and smoke-exposed mice. Together, these findings suggest a critical role for C3a through autocrine/paracrine induction of C3aR in the pathogenesis of cigarette smoke-induced sterile inflammation and provide new therapeutic targets for the treatment of emphysema.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: X
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: M
authors.initials: M
authors.lastname: Shan
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: R
authors.initials: R
authors.lastname: You
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: M V
authors.initials: MV
authors.lastname: Frazier
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Hong
authors.affiliation: Brown Foundation Institute of Molecular Medicine-Research Center for Immunology and Autoimmune Diseases, The University of Texas Medical School at Houston, Houston, Texas, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Wetsel
authors.affiliation: Brown Foundation Institute of Molecular Medicine-Research Center for Immunology and Autoimmune Diseases, The University of Texas Medical School at Houston, Houston, Texas, USA.
authors.forename: S
authors.initials: S
authors.lastname: Drouin
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: A
authors.initials: A
authors.lastname: Seryshev
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: L-Z
authors.initials: LZ
authors.lastname: Song
authors.affiliation: Department of Surgery, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cornwell
authors.affiliation: 1] Department of Medicine, Baylor College of Medicine, Houston, Texas, USA [2] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA [3] Michael E DeBakey VA Center for Translational Research on Inflammatory Diseases, Houston, Texas, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Rossen
authors.affiliation: 1] Department of Medicine, Baylor College of Medicine, Houston, Texas, USA [2] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA [3] Michael E DeBakey VA Center for Translational Research on Inflammatory Diseases, Houston, Texas, USA [4] Biology of Inflammation Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Corry
authors.affiliation: 1] Department of Medicine, Baylor College of Medicine, Houston, Texas, USA [2] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA [3] Michael E DeBakey VA Center for Translational Research on Inflammatory Diseases, Houston, Texas, USA [4] Biology of Inflammation Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: F
authors.initials: F
authors.lastname: Kheradmand
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D003167:Complement Activation; D003176:Complement C3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015926:Complement C3a / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004646:Emphysema / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D018345:Mice, Knockout; D019899:Paracrine Communication; D059748:Proteolysis; D011951:Receptors, Complement / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects*
chemical_list: D003176:Complement C3; D011951:Receptors, Complement; C085567:complement C3a receptor; D015926:Complement C3a; D019272:Leukocyte Elastase; D053508:Matrix Metalloproteinase 12