摘要
Cardiopulmonary complications are major drivers of mortality caused by the SARS-CoV-2 virus.Interleukin-18,an inflammasomeinduced 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.
基金
National Key Research and Development Program of China(2019YFE0119400)
Natural Science Foundation of China(81770059,81970052 and 82000055)
NIH NHLBI Grant(R01HL136603 to A.A.D.)
National Science Foundation CCF PIPP Grant(2200138 to J.S.C.)
ZHONGNANSHAN MEDICAL FOUNDATION OF GUANGDONG PROVINCE(ZNSA-2020013)
Shenzhen Science and Technology Program(JCYJ20210324122410028)
Open Project of State Key Laboratory of Respiratory Disease(SKLRD-OP-202301/202114).
