Abstract Fri034: Investigating the Role of IL-13 and ILC2s in Cardiac Macrophage Function and Myocarditis Resolution

Background: Myocarditis is an inflammatory heart disease often triggered by viral infections, autoimmunity, or environmental insults. While some patients recover, about 30% develop pathological cardiac remodeling, leading to dilated cardiomyopathy and heart failure. A hallmark of myocarditis is leukocyte infiltration, which disrupts immune homeostasis and depletes cardiac resident macrophages (MØ). These MØ are essential for maintaining immune balance and supporting tissue repair, yet the impact of inflammation on their function and composition remains poorly understood. Identifying mechanisms that preserve and restore MØ during inflammation is crucial for developing targeted therapies to prevent disease progression and promote recovery. Interleukin-13 (IL-13) is an immunoregulatory cytokine known to support tissue-resident MØ in other organs, but its role in cardiac immunity remains unclear. Innate lymphoid cells type 2 (ILC2s), a primary source of IL-13 in the heart, may be key regulators of MØ restoration, presenting a potential therapeutic target for myocarditis. Hypothesis: ILC2-derived IL13 signals to cardiac MØ, promoting their maintenance and phenotype, thereby reducing cardiac inflammation and enhancing myocardial recovery during myocarditis. Methods: We first used single-cell RNA sequencing (scRNA-seq) to assess whether cardiac ILC2s are key IL-13 producers during myocarditis and to examine their interactions with resident MØ. Next, we evaluated the impact of IL-13 loss on myocarditis progression using IL-13 knockout mice, analyzing disease severity and MØ composition and phenotype in the heart. Finally, we investigated the direct effects of IL-13 signaling on cardiac MØ using murine models lacking IL-4Rα (IL-13 receptor subunit) specifically in MØ. Results: Our preliminary data indicate that ILC2s are a primary source of IL-13 in the heart, while cardiac MØ express key IL-13 receptor subunits (IL4Rα and IL13Rα). Furthermore, IL-13 deficiency was found to exacerbate myocarditis severity, and genetic ablation of IL-4Rα specifically in MØ further worsens disease outcomes. This suggests a direct IL-13-mediated regulation of MØ during myocarditis development. Conclusions: This study aims to define IL-13 as a key immunoregulatory cytokine in the heart, regulating MØ maintenance and promoting myocardial recovery after inflammation. Understanding the interplay between ILC2s and cardiac MØ may reveal novel therapeutic targets for myocarditis.