Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis.
Cell Death Differ
; 29(2): 420-438, 2022 02.
Article
in English
| MEDLINE | ID: covidwho-1406388
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
STAT3 Transcription Factor
/
Cytokine Release Syndrome
/
COVID-19
/
Inflammation
Type of study:
Experimental Studies
/
Prognostic study
Limits:
Aged
/
Animals
/
Female
/
Humans
/
Male
/
Middle aged
Language:
English
Journal:
Cell Death Differ
Year:
2022
Document Type:
Article
Affiliation country:
S41418-021-00866-0
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