Activation of STING facilitates Kawasaki disease through mediating inflammation and apoptosis

Abstract Kawasaki disease (KD), a systemic febrile syndrome and acquired cardiac disease during childhood, is characterized by coronary arteritis. The immune response plays a crucial role in mediating KD progression. Due to the prevalence and severity of KD, more studies are required on its pathophysiology. Stimulator of interferon genes (STING) is an indispensable molecule that mediates inflammation and immune response in numerous diseases. However, its function during KD is still unknown. Here in our present study, we found that the contents of STING and its down-streaming molecules associated with inflammation and apoptosis were significantly up-regulated in serum of KD patients compared with the normal healthy individuals. Consistently, KD serum-incubated bone marrow-derived dendritic cells (BMDCs) exerted significantly up-regulated expression of STING both from gene and protein levels, indicating the importance of STING during KD progression. Subsequently, we found that STING-knockout significantly reduced the fibrosis and inflammatory response in a KD mouse model induced by Candida albicans cell wall extracts (CAWS), contributing to the improvements of cardiac function and survival rates of KD mice. Additionally, the activation of STING down-streaming signals including interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB/p65) was highly ameliorated by STING-deficiency in coronary lesions of CAWS-treated mice. Furthermore, apoptosis in heart sections was also remarkably attenuated upon STING-ablation, along with decreased expression of cleaved Caspase-3 in coronary lesions. Finally, our in vitro studies revealed that STING knockdown strongly rescued the cell viability of BMDCs with CAWS stimulation. Consistently, CAWS-induced inflammation and apoptotic cell death were dramatically meliorated in BMDCs upon STING suppression. Taken together, all these findings provided new evidence that STING might be a promising therapeutic target for KD treatment.