Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes

Cell. 2021 Jan 7;184(1):149-168.e17. doi: 10.1016/j.cell.2020.11.025. Epub 2020 Nov 19.


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-α and IFN-γ induced inflammatory cell death characterized by inflammatory cell death, PANoptosis. Mechanistically, TNF-α and IFN-γ co-treatment activated the JAK/STAT1/IRF1 axis, inducing nitric oxide production and driving caspase-8/FADD-mediated PANoptosis. TNF-α and IFN-γ 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-α and IFN-γ 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.

Keywords: COVID-19; IFN-γ; PANoptosis; SARS-CoV-2; TNF-α; apoptosis; cytokine storm; inflammation; necroptosis; pyroptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / administration & dosage
  • COVID-19 / immunology*
  • COVID-19 / pathology*
  • Cell Death
  • Cytokine Release Syndrome / immunology*
  • Cytokine Release Syndrome / pathology*
  • Disease Models, Animal
  • Female
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Inflammation / immunology
  • Inflammation / pathology
  • Interferon-gamma / immunology*
  • Lymphohistiocytosis, Hemophagocytic / chemically induced
  • Male
  • Mice
  • Mice, Transgenic
  • THP-1 Cells
  • Tumor Necrosis Factor-alpha / immunology*


  • Antibodies, Neutralizing
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma