TR4 worsen urosepsis by regulating GSDMD.

Area of Science:

• Immunology
• Molecular Biology
• Pathology

Background:

• Urosepsis is a severe condition caused by microbial invasion of the bloodstream, leading to immune dysregulation.
• Understanding the molecular mechanisms underlying urosepsis is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the role of testicular orphan receptor 4 (TR4) in the pathogenesis and progression of urosepsis.
• To elucidate the molecular pathways through which TR4 influences the immune response during urosepsis.

Main Methods:

• Analysis of clinical data and human samples to correlate TR4 expression with urosepsis outcomes.
• Establishment of an E. coli-induced urosepsis mouse model for in vivo studies.
• In vitro experiments to assess the impact of TR4 modulation on macrophage pyroptosis and Gasdermin D (GSDMD) expression.

Main Results:

• TR4 expression levels were higher in non-survivors compared to survivors of urosepsis.
• Overexpression of TR4 exacerbated inflammatory cytokine production, while TR4 knockdown reduced it.
• TR4 was found to promote macrophage pyroptosis by regulating GSDMD transcription, and its knockdown protected against E. coli-induced urosepsis in mice.

Conclusions:

• TR4 acts as a key regulator in urosepsis, primarily by mediating macrophage pyroptosis through GSDMD.
• Modulating TR4 activity presents a promising therapeutic avenue for managing urosepsis.