Natural killer cells suppress cardiac inflammation and fibrosis by inhibiting eosinophil accumulation
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Date
2014-07-30
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Johns Hopkins University
Abstract
Myocarditis is the inflammation of the cardiac muscle and a leading cause of sudden cardiac failure. Previously, our lab has shown that natural killer (NK) cells suppress group B coxsackievirus (CVB) and mouse cytomegalovirus (MCMV)-induced viral myocarditis severity by minimizing virus replication. We demonstrate that the protective capabilities of NK cells in myocarditis extend beyond controlling viral infection into directly controlling autoimmune-mediated inflammation. Experimental autoimmune myocarditis (EAM) is instigated in BALB/c mice by immunization with cardiac myosin peptide. NK cells accumulated in the heart through EAM, secreted IFNγ, perforin, and granzyme-B, and had upregulated levels of activation receptors compared to peripheral NK cells. Wildtype (WT) mice undergoing EAM showed significantly greater disease severity when NK cells were depleted using anti-asialo GM1 antibodies. This was accompanied by increased cardiac inflammation, collagen deposition, and a 10-fold increase in the proportion of infiltrating eosinophils. This increased influx of eosinophils was required for the effects of NK depletion in WT mice, indicating that NK cells control disease severity through the suppression of eosinophil infiltration. NK cells had the ability to control eosinophil-related chemokine expression from primary cardiac fibroblasts (CF) – levels of eotaxin 1 (CCL11), eotaxin 2 (CCL24), CXCL9, and CXCL10 were regulated by NK cells both in vivo and in vitro. Altogether, we show a new pathway of eosinophilic regulation through interactions with NK cells and open a new line of therapeutic research in the treatment of myocarditis.
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Keywords
natural killer cells, myocarditis