Activation of C3a receptor is required in cigarette smoke-mediated emphysema

X. Yuan, M. Shan, R. You, M. V. Frazier, M. J. Hong, R. A. Wetsel, S. Drouin, A. Seryshev, L. Z. Song, L. Cornwell, R. D. Rossen, D. B. Corry, F. Kheradmand

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)874-885
Number of pages12
JournalMucosal Immunology
Issue number4
StatePublished - Jul 25 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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