Liang, ShuxinBao, ChangleiYang, ZiLiu, ShiyunSun, YananCao, WeitaoWang, TingSchwantes-An, Tae-HwiChoy, John S.Naidu, SamisubbuLuo, AngYin, WenguangBlack, Stephen M.Wang, JianDesai, Ankit A.Tang, Haiyang2023-11-162023-11-162023-03-09Liang S, Bao C, Yang Z, et al. SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary inflammation via reduced mitophagy. Signal Transduct Target Ther. 2023;8(1):108. Published 2023 Mar 9. doi:10.1038/s41392-023-01368-whttps://hdl.handle.net/1805/37079Cardiopulmonary complications are major drivers of mortality caused by the SARS-CoV-2 virus. Interleukin-18, an inflammasome-induced cytokine, has emerged as a novel mediator of cardiopulmonary pathologies but its regulation via SARS-CoV-2 signaling remains unknown. Based on a screening panel, IL-18 was identified amongst 19 cytokines to stratify mortality and hospitalization burden in patients hospitalized with COVID-19. Supporting clinical data, administration of SARS-CoV-2 Spike 1 (S1) glycoprotein or receptor-binding domain (RBD) proteins into human angiotensin-converting enzyme 2 (hACE2) transgenic mice induced cardiac fibrosis and dysfunction associated with higher NF-κB phosphorylation (pNF-κB) and cardiopulmonary-derived IL-18 and NLRP3 expression. IL-18 inhibition via IL-18BP resulted in decreased cardiac pNF-κB and improved cardiac fibrosis and dysfunction in S1- or RBD-exposed hACE2 mice. Through in vivo and in vitro work, both S1 and RBD proteins induced NLRP3 inflammasome and IL-18 expression by inhibiting mitophagy and increasing mitochondrial reactive oxygenation species. Enhancing mitophagy prevented Spike protein-mediated IL-18 expression. Moreover, IL-18 inhibition reduced Spike protein-mediated pNF-κB and EC permeability. Overall, the link between reduced mitophagy and inflammasome activation represents a novel mechanism during COVID-19 pathogenesis and suggests IL-18 and mitophagy as potential therapeutic targets.en-USAttribution 4.0 InternationalCOVID-19InflammasomesInterleukin-18MitophagyCoronavirus spike glycoproteinArticle