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 to wild type mice. Proteolytic cleavage of C3 by neutrophil elastase releases C3a, which in turn increases 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.

Clinical and Immunological Factors in Emphysema Progression. Five-Year Prospective Longitudinal Exacerbation Study of Chronic Obstructive Pulmonary Disease (LES-COPD)

“…Specifically, active smokers who display autoreactive T cells with increased IFN-g and IL-6 responses to EFs show a higher rate of emphysema progression. These support recent studies in mice showing that prolonged exposure to smoke could lower the threshold for autoimmune inflammation and lung destruction (30,31). Importantly, our findings suggest novel means for detecting smokers who are at high risk for development and progression of emphysema and who might be suitable for early targeted therapeutic intervention.…”

“…The association of autoimmune responses with emphysema severity and progression is also supported by recent studies in mice showing that prolonged exposure to smoke could lower the threshold for autoimmune inflammation and lung destruction (30,31). Our findings of the potential association of elastin-specific immune responses with emphysema progression are of particular interest.…”

Neutrophils Induce Astroglial Differentiation and Migration of Human Neural Stem Cells via C1q and C3a Synthesis

“…5G). These data are consistent with early demonstrations of PMN-derived cationic and neutral protease C3 cleavage and C3a generation (60,61), as well as recent studies of ELANE C3 cleavage and C3a generation (59). Critically, in this regard, inhibition of C3a generation by EDTA in our data does not necessarily reflect C3 convertase inhibition, as EDTA has been shown to bind and inhibit ELANE (62).…”

“…5E), which, in combination with C3b membrane binding, amplifies convertase activity and C3a generation (54,56,57). Additionally, C3 can undergo direct cleavage by neutral and serine proteases, generating C3a (58,59). Finally, PMN secrete elastases (e.g., ELANE, Fig.…”

“…Finally, PMN secrete elastases (e.g., ELANE, Fig. 5E), and ELANE efficiently cleaves C3 into biologically active C3a (59). To test for fluid-phase C3a generation, purified C3 was added to cultured PMN in vitro and C3a measured by ELISA in PMN-CM.…”