Interleukin-13 Protects Against Experimental Autoimmune Myocarditis by Regulating Macrophage Differentiation

Daniela Cihakova^*, Jobert G. Barin^*, Marina Afanasyeva, Miho Kimura^*, DeLisa Fairweather^*, Michael Berg^¶, Monica V. Talor^*, G. Christian Baldeviano^¶, Sylvia Frisancho, Kathleen Gabrielson^||, Djahida Bedja^|| and Noel R. Rose^*^,¶

From the Departments of Pathology,^* and Molecular and Comparative Pathobiology,|| and the Graduate Program in Immunology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; the W. Harry Feinstone Department of Molecular Microbiology and Immunology,^¶ and the Department of Environmental Health Sciences, the Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland; and the Cardiovascular Research Group, Faculty of Medicine, University of Calgary, Calgary, Canada

We report here that interleukin (IL)-13 protects BALB/c micefrom myocarditis, whether induced by peptide immunization orby viral infection. In contrast to mild disease in IL-4 knockout(KO) BALB/c mice, IL-13 KO BALB/c mice developed severe coxsackievirusB3 (CVB3)-induced autoimmune myocarditis and myocarditogenicpeptide-induced experimental autoimmune myocarditis. Such severedisease was characterized by increased cardiac inflammation,increased total intracardiac CD45⁺ leukocytes, elevated anti-cardiacmyosin autoantibodies, and increased cardiac fibrosis. Echocardiographyrevealed that IL-13 KO mice developed severe dilated cardiomyopathywith impaired cardiac function and heart failure. Hearts ofIL-13 KO mice had increased levels of the proinflammatory andprofibrotic cytokines IL-1β, IL-18, interferon- ${gamma}$ , transforminggrowth factor-β1, and IL-4 as well as histamine. The hallmarkof the disease in IL-13 KO mice was the up-regulation of T-cellresponses. CD4⁺ T cells were increased in IL-13 KO hearts bothproportionally and in absolute number. Splenic T cells fromIL-13 KO mice were highly activated, and myosin stimulationadditionally increased T-cell proliferation. CD4⁺CD25⁺Foxp3⁺regulatory T-cell numbers were decreased in the spleens of IL-13KO mice. IL-13 deficiency led to decreased levels of alternativelyactivated CD206⁺ and CD204⁺ macrophages and increased levelsof classically activated macrophages. IL-13 KO mice had increasedcaspase-1 activation, leading to increased production of bothIL-1β and IL-18. Therefore, IL-13 protects against myocarditisby modulating monocyte/macrophage populations and by regulatingtheir function.