TNF‐α/IFN‐γ synergy amplifies senescence‐associated inflammation and SARS‐CoV‐2 receptor expression via hyper‐activated JAK/STAT1

• Published in: Aging cell Vol. 21; no. 6; pp. e13646 - n/a
• Main Authors: Kandhaya‐Pillai, Renuka, Yang, Xiaomeng, Tchkonia, Tamar, Martin, George M., Kirkland, James L., Oshima, Junko
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.06.2022; John Wiley and Sons Inc
• Subjects: ACE2; Aging; Angiotensin-converting enzyme 2; Chronic illnesses; Coronaviruses; COVID-19; COVID-19 - virology; COVID-19 Drug Treatment; Cytokine storm; cytokines; Cytokines - immunology; Diabetes; Diabetes mellitus; DPP4; Drug Synergism; Endothelial cells; Fibrosis; Gene expression; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Hypertension; Immune response; Immunosuppression; Infections; Inflammation; Inflammation - drug therapy; Inflammation - virology; Interferon; Interferon-gamma - pharmacology; Interleukin 6; Interleukin-6 - metabolism; JAK–STAT; Pathogenesis; Phenotypes; Proteins; Receptor mechanisms; Receptors, Virus - metabolism; Respiratory diseases; Risk factors; SARS-CoV-2 - drug effects; SARS-CoV-2 - metabolism; SARS‐COV‐2 receptor; Senescence; Severe acute respiratory syndrome coronavirus 2; Stat1 protein; STAT1 Transcription Factor - biosynthesis; STAT1 Transcription Factor - immunology; Tumor necrosis factor; Tumor Necrosis Factor-alpha - pharmacology; Umbilical vein; Viral infections; COVID-19; DPP4; senescence; ACE2; JAK-STAT; SARS-COV-2 receptor; inflammation; cytokines
• ISSN: 1474-9718; 1474-9726; 1474-9726
• DOI: 10.1111/acel.13646

Older age and underlying conditions such as diabetes/obesity or immunosuppression are leading host risk factors for developing severe complications from COVID‐19 infection. The pathogenesis of COVID‐19‐related cytokine storm, tissue damage, and fibrosis may be interconnected with fundamental aging processes, including dysregulated immune responses and cellular senescence. Here, we examined effects of key cytokines linked to cellular senescence on expression of SARS‐CoV‐2 viral entry receptors. We found exposure of human umbilical vein endothelial cells (HUVECs) to the inflammatory cytokines, TNF‐α + IFN‐γ or a cocktail of TNF‐α + IFN‐γ + IL‐6, increased expression of ACE2/DPP4, accentuated the pro‐inflammatory senescence‐associated secretory phenotype (SASP), and decreased cellular proliferative capacity, consistent with progression towards a cellular senescence‐like state. IL‐6 by itself failed to induce substantial effects on viral entry receptors or SASP‐related genes, while synergy between TNF‐α and IFN‐γ initiated a positive feedback loop via hyper‐activation of the JAK/STAT1 pathway, causing SASP amplification. Breaking the interactive loop between senescence and cytokine secretion with JAK inhibitor ruxolitinib or antiviral drug remdesivir prevented hyper‐inflammation, normalized SARS‐CoV‐2 entry receptor expression, and restored HUVECs proliferative capacity. This loop appears to underlie cytokine‐mediated viral entry receptor activation and links with senescence and hyper‐inflammation. TNF‐α and IFN‐γ synergistically enhanced expression of SARS‐CoV‐2 viral entry receptors, amplified senescence‐associated inflammation, and initiated a positive feedback loop via hyper‐activation of the JAK/STAT1 pathway in endothelial cells. Inhibition of JAK/STAT with ruxolitinib or antiviral remdesivir normalised ACE2/DDP4 expression and controlled hyper‐inflammation. Therapies with JAK inhibitors or drugs targeting JAK/STAT signaling could alleviate complications of cytokine storm in severe COVID‐19 infection.