No abstract

The involvement of macrophages in Th17 responses is still poorly understood. While neutrophils are thought to be the predominant effector of Th17 responses, IL17 is also known to induce myelotropic chemokines and growth factors. Other T cell-derived cytokines induce nonclassical functions, suggesting that IL17 signaling may similarly elicit unique macrophage functions. We characterized the expression of subunits of the IL17 receptor on primary murine macrophages from different anatomical compartments. The greatest expression of IL17 receptors was observed on mucosal Ly6Chi “inflammatory” macrophages. We further observed upregulation of IL17 receptors in vitro on bone marrow-derived macrophages in response to peptidoglycan or CpG oligonucleotide stimuli, and in vivo, upon CFA administration. Macrophages expressing IL17 receptors were observed infiltrating the hearts of mice with myocarditis, and genetic ablation of IL17RA altered macrophage recruitment. Treating primary macrophages from a wide variety of different anatomic sources (as well as cell lines) with IL17A induced the production of unique profiles of cytokines and chemokines, including GM-CSF, IL3, IL9, CCL4/MIP1β and CCL5/RANTES. IL17A also induced production of IL12p70; IL17-signaling deficient macrophages elicited diminished IFNγ production by responding DO11.10 CD4+ cells when used as APCs. These data indicate that macrophages from different anatomic locations direct IL17-mediated responses.

CD4+ T cells play a central role in inflammatory heart disease, implicating a cytokine product associated with helper T cell effector function as a necessary mediator of this pathophysiology. IFNγ-deficient mice developed severe autoimmune myocarditis (EAM), in which mice are immunized with cardiac myosin peptide, while IL17A-deficient mice were protected from progression to dilated cardiomyopathy. We generated IFNγ−/−IL17A−/− mice to assess whether IL17 signaling was responsible for the severe EAM of IFNγ−/− mice. Surprisingly, IFNγ−/−IL17A−/− mice developed a rapidly fatal EAM. Eosinophils comprised a third of infiltrating leukocytes, qualifying this disease eosinophilic myocarditis. We found increased cardiac production of CCL11/eotaxin, and Th2 deviation among heart-infiltrating CD4+ cells. Ablation of eosinophil development improved survival of IFNγ−/−IL17A−/− mice, demonstrating the necessity of eosinophils in fatal heart failure. The severe and rapidly fatal autoimmune inflammation that developed in the combined absence of IFNγ and IL17A constitutes a novel model of eosinophilic heart disease in humans. This is also the first demonstration that eosinophils have the capacity to act as necessary mediators of morbidity in an autoimmune process.