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Cell death and differentiation
02, 2022;29 (2): 420-438.

Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis.

Chiara Musiu, Simone Caligola, Alessandra Fiore, Alessia Lamolinara, Cristina Frusteri, Francesco Domenico Del Pizzo, Francesco De Sanctis, Stefania Canè, Annalisa Adamo, Francesca Hofer, Roza Maria Barouni, Andrea Grilli, Serena Zilio, Paolo Serafini, Evelina Tacconelli, Katia Donadello, Leonardo Gottin, Enrico Polati, Domenico Girelli, Ildo Polidoro, Piera Amelia Iezzi, Domenico Angelucci, Andrea Capece, Ying Chen, Zheng-Li Shi, Peter J Murray, Marco Chilosi, Ido Amit, Silvio Bicciato, Manuela Iezzi, Vincenzo Bronte, Stefano Ugel
Author Information
  1. Chiara Musiu: Immunology Section, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy. ORCID
  2. Simone Caligola: Immunology Section, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy. ORCID
  3. Alessandra Fiore: Immunology Section, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy.
  4. Alessia Lamolinara: CAST - Center for Advanced Studies and Technology, Department of Neurosciences Imaging and Clinical Sciences, University of G. D'Annunzio of Chieti-Pescara, Chieti, Italy.
  5. Cristina Frusteri: Immunology Section, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy.
  6. Francesco Domenico Del Pizzo: CAST - Center for Advanced Studies and Technology, Department of Neurosciences Imaging and Clinical Sciences, University of G. D'Annunzio of Chieti-Pescara, Chieti, Italy.
  7. Francesco De Sanctis: Immunology Section, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy.
  8. Stefania Canè: Immunology Section, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy.
  9. Annalisa Adamo: Immunology Section, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy.
  10. Francesca Hofer: Immunology Section, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy.
  11. Roza Maria Barouni: Immunology Section, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy.
  12. Andrea Grilli: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
  13. Serena Zilio: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA.
  14. Paolo Serafini: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA.
  15. Evelina Tacconelli: Division of Infectious Diseases, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy.
  16. Katia Donadello: Intensive Care Unit, Department of Surgery, Dentistry, Maternity and Infant, University and Hospital Trust of Verona, Verona, Italy.
  17. Leonardo Gottin: Intensive Care Unit, Department of Surgery, Dentistry, Maternity and Infant, University and Hospital Trust of Verona, Verona, Italy.
  18. Enrico Polati: Intensive Care Unit, Department of Surgery, Dentistry, Maternity and Infant, University and Hospital Trust of Verona, Verona, Italy.
  19. Domenico Girelli: Division of Internal Medicine, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy.
  20. Ildo Polidoro: Complex Operational Unit of Forensic Medicine, Local Health Authority of Pescara, Pescara, Italy.
  21. Piera Amelia Iezzi: Complex Operational Unit of Forensic Medicine, Local Health Authority of Pescara, Pescara, Italy.
  22. Domenico Angelucci: Pathological Anatomy Unit, Local Health Authority of Lanciano-Vasto-Chieti, Vasto, Italy.
  23. Andrea Capece: Pathological Anatomy Unit, Local Health Authority of Lanciano-Vasto-Chieti, Vasto, Italy.
  24. Ying Chen: CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, People's Republic of China.
  25. Zheng-Li Shi: CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, People's Republic of China. ORCID
  26. Peter J Murray: Max Planck Institute of Biochemistry, Martinsried, Planegg, Germany.
  27. Marco Chilosi: Department of Pathology, Pederzoli Hospital, Peschiera del Garda, Italy.
  28. Ido Amit: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
  29. Silvio Bicciato: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy. ORCID
  30. Manuela Iezzi: CAST - Center for Advanced Studies and Technology, Department of Neurosciences Imaging and Clinical Sciences, University of G. D'Annunzio of Chieti-Pescara, Chieti, Italy. ORCID
  31. Vincenzo Bronte: Immunology Section, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy. vincenzo.bronte@univr.it. ORCID
  32. Stefano Ugel: Immunology Section, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy. stefano.ugel@univr.it. ORCID
PMID: 34518653 DOI: 10.1038/s41418-021-00866-0

Abstract

Inflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-CoV-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homolog in myeloid cells triggered a STAT3-linked, progressive, and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury, and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state.

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Grants

  1. CLIP 2020/Cancer Research Institute (CRI)
  2. B38D19000260006/Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
  3. B38D19000140006/Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
  4. 23788/Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
  5. 21509/Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
  6. Enact/Fondazione Cassa di Risparmio di Verona Vicenza Belluno e Ancona (Fondazione Cariverona)

MeSH Term

Aged
Aged, 80 and over
Animals
COVID-19
Caspase 8
Cytokine Release Syndrome
Cytokines
Female
Humans
Inflammation
Male
Mice
Mice, Inbred C57BL
Middle Aged
SARS-CoV-2
STAT3 Transcription Factor
Signal Transduction

Chemicals

Cytokines
STAT3 Transcription Factor
Stat3 protein, mouse
Caspase 8
Journal Article Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

GEN: GEND000366 (Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis)

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