FXR protects against neonatal sepsis by enhancing the immunosuppressive function of MDSCs

Area of Science:

• Immunology
• Neonatal Medicine
• Molecular Biology

Background:

• Myeloid-derived suppressor cells (MDSCs) are crucial for neonatal immune homeostasis and protection against inflammation.
• The precise molecular mechanisms governing neonatal MDSC function are not fully understood.
• Understanding these mechanisms is vital for developing targeted therapies for neonatal conditions.

Purpose of the Study:

• To investigate the role of the bile acid receptor, farnesoid X receptor (FXR), in regulating neonatal MDSC function.
• To explore the therapeutic potential of FXR agonists in treating neonatal sepsis.

Main Methods:

• Utilized genetic models (Fxr knockout and conditional knockout mice) to assess FXR's role in MDSC function.
• Administered obeticholic acid (OCA), an FDA-approved FXR agonist, to evaluate its protective effects in a neonatal sepsis model.
• Performed adoptive transfer of MDSCs to confirm their therapeutic efficacy.
• Investigated the molecular link between FXR and Hif1α in MDSCs.

Main Results:

• FXR was identified as a positive regulator of neonatal MDSC function.
• OCA treatment demonstrated FXR-dependent protection against neonatal sepsis.
• Genetic deficiency of FXR impaired MDSC immunosuppressive and antibacterial functions, worsening sepsis severity.
• Adoptive transfer of MDSCs ameliorated sepsis in relevant genetic models.
• Hif1α was confirmed as a direct transcriptional target of FXR.
• Downregulation of FXR and HIF-1α in MDSCs from neonatal sepsis patients correlated inversely with clinical severity.

Conclusions:

• FXR plays a critical role in maintaining neonatal MDSC function and immune defense.
• Targeting FXR represents a promising therapeutic strategy for neonatal sepsis.
• The FXR-Hif1α axis is a key pathway regulating MDSC function in the neonatal period.