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Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis

Chiara Musiu1, Simone Caligola1, Alessandra Fiore1,2

  • 1Immunology Section, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy.

Cell Death and Differentiation
|September 14, 2021
PubMed

Insights

FLIP protein fuels cytokine release syndrome (CRS) by activating STAT3 inflammatory pathways. Targeting STAT3 alleviates CRS symptoms, offering a potential therapeutic strategy for this life-threatening condition.

Area of Science:

  • Immunology
  • Pathophysiology
  • Molecular Biology

Background:

  • Inflammatory responses are crucial for pathogen detection but can become dysregulated.
  • Cytokine release syndrome (CRS) is a life-threatening inflammatory pathology.
  • The pathophysiology of CRS, particularly in COVID-19, remains unclear.

Purpose of the Study:

  • To investigate the role of FLIP protein in CRS.
  • To elucidate the molecular mechanisms underlying CRS.
  • To identify potential therapeutic targets for CRS.

Main Methods:

  • Examined FLIP protein expression in myeloid cells from COVID-19 lungs.
  • Utilized a mouse model with constitutive expression of a viral FLIP homolog.
  • Assessed the impact of STAT3-targeting interventions in the mouse model.

Main Results:

  • FLIP was highly expressed in myeloid cells of COVID-19 lungs and fueled a STAT3-dependent inflammatory program.
  • Constitutive FLIP expression in mice induced a fatal inflammatory syndrome mimicking human CRS.
  • STAT3-targeting approaches ameliorated inflammation, immune disorders, and organ failures in mice.

Conclusions:

  • FLIP plays a critical role in CRS pathogenesis by activating STAT3.
  • Targeting the STAT3 pathway presents a promising therapeutic strategy for suppressing lethal CRS.
  • Understanding FLIP-STAT3 interactions is key to managing severe inflammatory conditions.

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