Abstract 4347786: Targeting the interleukin-33/ST2 Pathway Attenuates Coronary Arteritis in a Murine Model of Kawasaki Disease

Abstract

Background: Kawasaki disease (KD) is a systemic vasculitis that primarily affects young children and can result in coronary artery sequelae. The innate immune system plays an essential role in the development of vasculitis in KD. We previously reported that the regulatory mechanisms of the interleukin (IL)-33/suppression of tumorigenicity 2 (ST2) axis in innate immunity might be involved in KD pathophysiology in vitro . Hypothesis: Therapeutic strategies targeting the IL-33/ST2 axis may ameliorate coronary arteritis in KD. Methods: Using an established murine model of KD that involves injection of the NOD1 ligand FK565, we investigated the role of the IL-33/ST2 axis in coronary arteritis and evaluated the efficacy of treatments targeting the IL-33/ST2 axis as a novel therapeutic approach. Results: FK565-injected mice exhibited an increased number of IL-33–positive cells in coronary artery tissue. Both the anti-IL-33 antibody and ST2-Fc attenuated the FK565-induced coronary arteritis. Notably, ST2-Fc exhibited a more pronounced anti-inflammatory effect than the anti-IL-33 antibody. Bulk RNA-seq analysis of heart tissue showed that antigen processing and presentation, cytokine–cytokine receptor interaction, and IL-17 signaling pathways were significantly suppressed by the IL-33/ST2 axis-targeting therapies. Conclusion: These results indicate that IL-33/ST2 axis play a critical role in the development of coronary arteritis in KD via the crosstalk between innate and adaptive immunity. Therapeutic strategies targeting the IL-33/ST2 axis may represent an effective and targeted approach for preventing coronary artery lesions in KD.