SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary inflammation via reduced mitophagy.
Signal Transduct Target Ther
; 8(1): 108, 2023 03 09.
Article
in English
| MEDLINE | ID: covidwho-2268983
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Spike Glycoprotein, Coronavirus
/
COVID-19
Type of study:
Prognostic study
Limits:
Animals
/
Humans
Language:
English
Journal:
Signal Transduct Target Ther
Year:
2023
Document Type:
Article
Affiliation country:
S41392-023-01368-w
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