Abstract
Abstract Deviation to autoaggressive T helper 17 (Th17) responses has been reported to account for the protective effect of interferon-gamma (IFNγ) in certain animal models of autoimmune disease. Building on our previous findings that interleukin-17 (IL17) signaling is critical for the progression of experimental autoimmune myocarditis (EAM) to dilative heart failure, we sought to address the question of whether IL17 mediated the severe form of EAM observed in IFNγ-deficient mice. To our surprise, we found that IFNγ-/-IL17A-/- double-knockout (DKO) mice had greater mortality compared to IFNγ-/- mice, starting at day 14 and reaching 50% by day 21 of EAM. DKO hearts were severely infiltrated, indicating acute inflammatory heart failure as the mode of death in these mice. We found pronounced eosinophilic infiltration in DKO mice, implicating eosinophils as mediators of the enhanced morbidity. Cardiac production of CCL11/eotaxin was increased, alongside Th2 deviation among heart-infiltrating CD4+ T cells. Intriguingly, blockade of IL4 in IFNγ-/-IL17A-/-DKO mice inhibited Th2 deviation, but failed to resolve eosinophilia or morbidity. However, developmental ablation of eosinophils partly rescued the survival of DKO mice. These data point to a novel collaboration between IFNγ and IL17A in controlling eosinophil recruitment.
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