Fatal Eosinophilic Myocarditis Develops in the Absence of IFN-γ and IL-17A

Abstract

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.

Natural Killer Cells Limit Cardiac Inflammation and Fibrosis by Halting Eosinophil Infiltration

“…56 Similarly, IFNg À/À Il17A À/À mice display massively inflamed hearts and up to 50% fatality by day 21 of EAM, a phenotype that is reversed in the absence of eosinophils by crossing these animals to dblGATA1 mice. 57 Although the numbers of eosinophils infiltrating the heart after NK cell depletion (10% to 15%) during EAM do not approach clinical or animal models of eosinophilic myocarditis (up to 50%), we clearly demonstrate that even this moderate increase has significant consequences on disease outcome. 56,57 Clinically, infiltrating eosinophils are found in severe giant cell myocarditis and these patients, along with necrotizing eosinophilic myocarditis, have poor clinical prognosis.…”

Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis

“…when autoagressive CD4 + T cells usually infiltrate cardiac tissues) reduced cardiac MHCII expression and disease severity suggests that once the Th1/Th17 balance is established upon activation of autoreactive CD4 + T cells in lymphoid organs, IFN-γ contributes to cardiac pathology via the upregulation of nonhematopoietic MHCII expression. Interestingly, the strongest EAM phenotype leading to rapid lethality was observed in IFN-γ−/− IL-17A−/− mice, which developed EAM characterized by cardiac eosinophil infiltration and Th2 polarization [43]. This result argues for a greater redundancy among autoinflammatory T-cell subsets in EAM than expected previously and suggests that all Th subsets require precise balancing in order to avoid exacerbated, progressive pathology.…”

“…However, those mice lack the chronic phase characterized by fibrosis and impairment of cardiac function (termed DCM), which usually occurs in WT mice around days 40 to 70 [7,44]. Therefore, IL-17A is not essential for the early-stage inflammatory process of acute EAM [43,44]. Hence in the WT setting, IFN-γ may have an important part in the establishment of acute EAM while IL-17A has an essential role in profibrotic remodeling, chronicity, and progression to DCM.…”

“…Hence in the WT setting, IFN-γ may have an important part in the establishment of acute EAM while IL-17A has an essential role in profibrotic remodeling, chronicity, and progression to DCM. The protective effect of IFN-γ observed in mice deficient in IFN-γ or its receptor [6,22] is thus likely to be due mainly to the facts that (i) IFN-γ confines activated CD4 + T-cell expansion via nitric oxide [34], (ii) IFN-γ is involved in regulating CD4 + T-cell activation and apoptosis [31], and (iii) IFN-γ suppresses exacerbating Th17 responses [41][42][43], and thus to be unrelated to the IFN-γ-induced MHCII expression addressed in our study. Remarkably, two reports applying distinct models of spontaneous EAM, which are not based on immunization with α-MyHC, proposed that IFN-γ is driving the initial inflammatory phase of EAM [19,20].…”

“…Finally, T-bet−/− mice, which are impaired in Th1 differentiation, exhibited enhanced disease severity [40]. However, T-bet−/− mice exhibited increased IL-17 production [40] suggesting that exacerbated EAM was a consequence of abnormally increased Th17 responses [41][42][43]. It is therefore likely that Th17 cells only become dominant players in EAM in the absence of functional Th1 cells and IFN-γ signalling.…”