SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary inflammation via reduced mitophagy.

Abstract

Cardiopulmonary 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.

• Authors: Shuxin Liang, Changlei Bao, Zi Yang, Shiyun Liu, Yanan Sun, Weitao Cao, Ting Wang, Tae-Hwi Schwantes-An, John S Choy, Samisubbu Naidu, Ang Luo, Wenguang Yin, Stephen M Black, Jian Wang, Pixin Ran, Ankit A Desai, Haiyang Tang
• Journal: Signal transduction and targeted therapy (Signal Transduct Target Ther) Vol. 8 Issue 1 Pg. 108 (03 09 2023) ISSN: 2059-3635 [Electronic] England
• PMID: 36894537 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2023. The Author(s).

Chemical References

• spike protein, SARS-CoV-2
• Spike Glycoprotein, Coronavirus
• Inflammasomes
• Interleukin-18
• NLR Family, Pyrin Domain-Containing 3 Protein
• Cytokines

Topics

• Humans
• Mice
• Animals
• Spike Glycoprotein, Coronavirus (metabolism)
• SARS-CoV-2 (metabolism)
• COVID-19 (genetics)
• Inflammasomes (genetics, metabolism)
• Interleukin-18 (genetics)
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, metabolism)
• Mitophagy (genetics)
• Inflammation (genetics, metabolism)
• Cytokines