Cell, 2021-01, Vol.184 (1), p.149-168.e17
2021
Details
- Autor(en) / Beteiligte
- Titel
- Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes
- Ist Teil von
- Cell, 2021-01, Vol.184 (1), p.149-168.e17
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2021
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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. [Display omitted] •Of several cytokines tested, only synergism of TNF-α and IFN-γ induces PANoptosis•TNF-α and IFN-γ-mediated PANoptosis perpetuates cytokine storm•TNF-α and IFN-γ shock mirrors cytokine storm syndromes, including COVID-19•Neutralizing TNF-α and IFN-γ protects against SARS-CoV-2, HLH, and sepsis in mice TNF-α and IFN-γ synergize to drive the cytokine storm and cell death associated with COVID-19 and sepsis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0092-8674eISSN: 1097-4172DOI: 10.1016/j.cell.2020.11.025Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7674074
- Format
- –
- Schlagworte
- Animals, Antibodies, Neutralizing - administration & dosage, apoptosis, Cell Death, COVID-19, COVID-19 - immunology, COVID-19 - pathology, Cytokine Release Syndrome - immunology, Cytokine Release Syndrome - pathology, cytokine storm, Disease Models, Animal, Female, Human Umbilical Vein Endothelial Cells, Humans, IFN-γ, inflammation, Inflammation - immunology, Inflammation - pathology, Interferon-gamma - immunology, Lymphohistiocytosis, Hemophagocytic - chemically induced, Male, Mice, Mice, Transgenic, necroptosis, PANoptosis, pyroptosis, SARS-CoV-2, THP-1 Cells, TNF-α, Tumor Necrosis Factor-alpha - immunology