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

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.

SUBMITTER: Musiu C

PROVIDER: S-EPMC8435761 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Musiu Chiara C Caligola Simone S Fiore Alessandra A Lamolinara Alessia A Frusteri Cristina C Del Pizzo Francesco Domenico FD De Sanctis Francesco F Canè Stefania S Adamo Annalisa A Hofer Francesca F Barouni Roza Maria RM Grilli Andrea A Zilio Serena S Serafini Paolo P Tacconelli Evelina E Donadello Katia K Gottin Leonardo L Polati Enrico E Girelli Domenico D Polidoro Ildo I Iezzi Piera Amelia PA Angelucci Domenico D Capece Andrea A Chen Ying Y Shi Zheng-Li ZL Murray Peter J PJ Chilosi Marco M Amit Ido I Bicciato Silvio S Iezzi Manuela M Bronte Vincenzo V Ugel Stefano S

Cell death and differentiation 20210913 2

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 COV ...[more]

PMID: 34518653

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Project description:Background and purposeNeurological manifestations in coronavirus disease (COVID)-2019 may adversely affect clinical outcomes. Severe COVID-19 and uremia are risk factors for neurological complications. However, the lack of insight into their pathogenesis, particularly with respect to the role of the cytokine release syndrome (CRS), is currently hampering effective therapeutic interventions. The aims of this study were to describe the neurological manifestations of patients with COVID-19 and to gain pathophysiological insights with respect to CRS.MethodsIn this longitudinal study, we performed extensive clinical, laboratory and imaging phenotyping in five patients admitted to our renal unit.ResultsNeurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Notably, neurological disturbances were accompanied by laboratory evidence of CRS. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was undetectable in the cerebrospinal fluid (CSF). Hyperalbuminorrachia and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain magnetic resonance imaging findings comprised evidence of acute leukoencephalitis (n = 3, one of whom had a hemorrhagic form), cytotoxic edema mimicking ischaemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted, resulting in rapid recovery from neurological disturbances in two cases. SARS-CoV2 was undetectable in 88 of the 90 patients with COVID-19 who underwent Reverse Transcription-PCR testing of CSF.ConclusionsPatients with COVID-19 can develop neurological manifestations that share clinical, laboratory and imaging similarities with those of chimeric antigen receptor T-cell-related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.

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

Publications

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

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