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Macrophages participate in IL-17-mediated inflammation

Barin, JG;Baldeviano, GC;Talor, MV;Wu, L;Ong, S;Quader, F;Chen, P;Zheng, D;Caturegli, P;Rose, NR;Cihkov, D;

The involvement of macrophages (Ms) 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 M functions. Here, we characterized the expression of subunits of the IL-17 receptor on primary murine Ms from different anatomical compartments. The greatest expression of IL-17 receptors was observed on mucosal Ly6C(hi) inflammatory Ms. We further observed upregulation of IL-17 receptors in vitro on bone marrow-derived macrophages (BMMs) 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 M recruitment. Treating primary Ms 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 and CCL5/RANTES. IL-17A also induced production of IL-12p70; IL-17-signaling-deficient Ms elicited diminished IFN- production by responding DO11.10 CD4(+) T cells when used as APCs. These data indicate that Ms from different anatomic locations direct IL-17-mediated responses.