Therapeutic Administration of the Chemokine CXCL1/KC Abrogates Autoimmune Inflammatory Heart Disease
نویسندگان
چکیده
Myocarditis, often due to an aberrant immune response to infection, is a major cause of dilated cardiomyopathy. Microbial pattern recognition receptors, such as TLRs, orchestrate the cytokine and chemokine responses that augment or limit the severity of myocarditis. Using the mouse model of experimental autoimmune myocarditis (EAM), in which disease is induced by immunization with a heart-specific self peptide and the agonist to multiple TLRs, complete Freund's adjuvant, we found that increased serum concentrations of the chemokine CXCL1/KC correlated directly with decreased severity of myocarditis. To directly test whether CXCL1/KC caused the amelioration of myocarditis, we treated mice, after challenge with heart-specific self peptide, with exogenous recombinant CXCL1/KC. We found that the administration of recombinant mouse CXCL1/KC completely abrogated heart inflammatory infiltration and cardiomyocyte damage. Moreover, we show that TLR4 signaling is required to increase serum protein concentrations of CXCL1/KC in EAM, and we demonstrate that the administration of the TLR4 agonist LPS significantly decreased severity and prevalence of EAM and reduced the number of heart-specific self peptide reactive effector T cells. These findings reveal a novel function of CXCL1/KC in the context of organ-specific autoimmune disease that may prove useful for the treatment of inflammatory conditions that underlie human heart disease.
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