Differential requirement of C3a receptor in APC-driven emphysema in response to cigarette smoke (P6225)

Abstract

Abstract Pathogenic lung antigen presenting cells (APCs) are abundant in the lungs of smokers with emphysema and are capable of inducing T helper type 1 (Th1) and Th17 cell differentiation. Mice exposed to chronic cigarette smoke develop emphysema and harbor CD11b+CD11c+ APCs that can transfer the disease to naïve mice. Proteolytic products from activated innate immune cells cleave complement proteins but the contribution of their downstream signaling in APC-driven lung parenchyma destruction is less clear. We show here that relative to control smokers, complement 3 (C3) is increased in the plasma and its cleaved products are deposited on the lung tissue of smokers with advanced lung disease. Matrix metalloproteinase 12 and neutrophils elastase directly cleave human C3, and generate multiple activated signaling products. Compared to wild type, C3 deficient mice exposed to chronic smoke showed reduced CD11b+CD11c+ cells in the lungs and were protected against emphysema development. C3a and C5a, two of the major anaphylatoxin and chemoattractant mediators downstream of C3 activation, are present in the lungs of mice exposed to smoke, but only C3a signaling was critical in emphysema development because deficiency in C3a receptor (C3aR) but not C5aR phenocopied C3-/- mice in this model. These findings suggest a critical role for C3aR in the pathogenesis of smoke induced lung disease, and could be explored to develop specific new therapeutic targets for emphysema treatment.