Macrophages participate in IL-17-mediated inflammation

The involvement of macrophages (MFs) in Th17-cell responses is still poorly understood. While neutrophils are thought to be the predominant effector of Th17-cell responses, IL-17 is also known to induce myelotropic chemokines and growth factors. Other T-cell-derived cytokines induce non-classical functions, suggesting that IL-17 sigxnaling may similarly elicit unique MF functions. Here, we characterized the expression of subunits of the IL-17 receptor on primary murine MFs from different anatomical compartments. The greatest expression of IL-17 receptors was observed on mucosal Ly6Chi inflammatory MFs. We further observed upregulation of IL-17 receptors in vitro on bone marrow-derived macrophages (BMMFs) in response to peptidoglycan or CpG oligonucleotide stimuli, and in vivo, upon CFA administration. Macrophages expressing IL-17 receptors were observed infiltrating the hearts of mice with myocarditis, and genetic ablation of IL-17RA altered MF recruitment. Treating primary MFs from a wide variety of different anatomic sources (as well as cell lines) with IL-17A induced the production of unique profiles of cytokines and chemokines, including GM-CSF, IL-3, IL-9, CCL4/MIP-1 beta and CCL5/RANTES. IL-17A also induced production of IL-12p70; IL-17-signaling-deficient MFs elicited diminished IFN-? production by responding DO11.10 CD4+ T cells when used as APCs. These data indicate that MFs from different anatomic locations direct IL-17-mediated responses.