| First Author | Karki R | Year | 2021 |
| Journal | Cell | Volume | 184 |
| Issue | 1 | Pages | 149-168.e17 |
| PubMed ID | 33278357 | Mgi Jnum | J:361144 |
| Mgi Id | MGI:7855991 | Doi | 10.1016/j.cell.2020.11.025 |
| Citation | Karki R, et al. (2021) Synergism of TNF-alpha and IFN-gamma Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes. Cell 184(1):149-168.e17 |
| abstractText | COVID-19 is characterized by excessive production of pro-inflammatory cytokines and acute lung damage associated with patient mortality. While multiple inflammatory cytokines are produced by innate immune cells during SARS-CoV-2 infection, we found that only the combination of TNF-alpha and IFN-gamma induced inflammatory cell death characterized by inflammatory cell death, PANoptosis. Mechanistically, TNF-alpha and IFN-gamma co-treatment activated the JAK/STAT1/IRF1 axis, inducing nitric oxide production and driving caspase-8/FADD-mediated PANoptosis. TNF-alpha and IFN-gamma caused a lethal cytokine shock in mice that mirrors the tissue damage and inflammation of COVID-19, and inhibiting PANoptosis protected mice from this pathology and death. Furthermore, treating with neutralizing antibodies against TNF-alpha and IFN-gamma protected mice from mortality during SARS-CoV-2 infection, sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock. Collectively, our findings suggest that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other infectious and autoinflammatory diseases by limiting tissue damage/inflammation. |
