Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis.
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
06
05
2021
accepted:
31
08
2021
revised:
30
08
2021
pubmed:
15
9
2021
medline:
1
3
2022
entrez:
14
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34518653
doi: 10.1038/s41418-021-00866-0
pii: 10.1038/s41418-021-00866-0
pmc: PMC8435761
doi:
Substances chimiques
Cytokines
0
STAT3 Transcription Factor
0
Stat3 protein, mouse
0
Caspase 8
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
420-438Subventions
Organisme : Cancer Research Institute (CRI)
ID : CLIP 2020
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
ID : B38D19000260006
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
ID : B38D19000140006
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : 23788
Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)
ID : 21509
Organisme : Fondazione Cassa di Risparmio di Verona Vicenza Belluno e Ancona (Fondazione Cariverona)
ID : Enact
Informations de copyright
© 2021. The Author(s).
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