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

Abstract

Myocarditis is a leading cause of sudden cardiac failure in young adults. Natural killer (NK) cells, a subset of the innate lymphoid cell compartment, are protective in viral myocarditis. Herein, we demonstrated that these protective qualities extend to suppressing autoimmune inflammation. Experimental autoimmune myocarditis (EAM) was initiated in BALB/c mice by immunization with myocarditogenic peptide. During EAM, activated cardiac NK cells secreted interferon γ, perforin, and granzyme B, and expressed CD69, tumor necrosis factor-related apoptosis-inducing ligand treatment, and CD27 on their cell surfaces. The depletion of NK cells during EAM with anti-asialo GM1 antibody significantly increased myocarditis severity, and was accompanied by elevated fibrosis and a 10-fold increase in the percentage of cardiac-infiltrating eosinophils. The resultant influx of eosinophils to the heart was directly responsible for the increased disease severity in the absence of NK cells, because treatment with polyclonal antibody asialogangloside GM-1 did not augment myocarditis severity in eosinophil-deficient ΔdoubleGATA1 mice. We demonstrate that NK cells limit eosinophilic infiltration both indirectly, through altering eosinophil-related chemokine production by cardiac fibroblasts, and directly, by inducing eosinophil apoptosis in vitro. Altogether, we define a new pathway of eosinophilic regulation through interactions with NK cells.

Cannabidiol Limits T Cell-Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation

“…Consistent with previous investigations (8,10,20,25), we found that immunization with the MyHCα 334-352 of mice resulted in severe inflammatory cell infiltration and necrosis on H&E-stained myocardial sections. Autoimmune myocarditis is considered to be a disease primarily driven by T-cell activation induced by cardiac myosin release (29).…”

“…CBD treatment protected against cisplatin-induced kidney injury in a mouse model, in which the complement system activation plays an important role in mediating inflammation and tissue injury oxidase isoform p47phox associated with the autoimmune inflammation, as well as improved the downregulation of SERCA mRNA. Fibrotic remodeling of the myocardium is a well-known consequence of EAM (8,10). Consistent with previous studies, we observed marked fibrotic remodeling in the heart of EAM mice.…”

“…In different pathologies where the heart is injured (microbial infections, toxins, ischemic infarction and so on), the dendritic cells residing in the cardiac draining lymph nodes become activated and start to present MyHCα to naive T cells specific for MyHCα. In the pathogenesis of autoimmune myocarditis (in mice or humans), these T lymphocytes play a leading role either by their direct cytotoxic effects or by inducing B cells to produce pathogenic antibodies (7), leading to necrosis, oxidative stress, fibrotic remodeling and myocardial dysfunction (8)(9)(10). Although, a wide range of specific and nonspecific drugs could be used to treat myocarditis on the basis of etiology, the conventional immunosuppressive and heart failure therapies often provide partial and/or unsatisfactory results.…”

Viral myocarditis

“…Moreover, IL17, a cytokine considered important in inflammation, regulates the severity of myocarditis in interferon gamma deprived animals so that they rapidly develop a fatal eosinophilic disease, providing the first mouse model for testing treatments of human eosinophilic myocarditis (29). NK cells, prominent members of the innate immune response, also limit autoimmune mediated information and fibrosis perhaps by downregulating IL17 producing T cells (30*). Most surprisingly IL17 has little impact on the severity of autoimmune myocarditis but is essential for progression to dilated cardiomyopathy (31).…”

Natural killer cells in inflammatory heart disease

“…However, blockade of NK cells and their receptors can protect against inflammation and damage in animal models of cardiac injury and inflammation. In these models, NK cells suppress the maturation and trafficking of inflammatory cells, alter the local cytokine and chemokine environments, and induce apoptosis in nearby resident and hematopoietic cells [1, 9, 10]. This review will dissect each protective mechanism employed by NK cells and explore how their properties might be exploited for their therapeutic potential.…”