SREBF1 mediates immunoparalysis of dendritic cells in sepsis by regulating lipid metabolism and endoplasmic reticulum stress.

BACKGROUND

Lipid metabolic reprogramming is a key feature of sepsis, with increased lipid storage contributing to disease progression. Although lipid metabolism dysregulation has been implicated in sepsis pathogenesis, how lipid biosynthesis, particularly mediated by sterol regulatory element-binding transcription factor 1 (SREBF1), leads to dendritic cell (DC) immunoparalysis remains unclear.

METHODS

Intracellular lipid accumulation was assessed by Oil Red O and BODIPY staining. Gene and protein expression levels were analyzed via qPCR, Western blot, and immunofluorescence. SREBF1 activity was modulated using genetic knockout and siRNA silencing. DC phenotype and CD4+ T cell proliferation were evaluated using flow cytometry and co-culture assays. Cytokine secretion was measured using ELISA.

RESULTS

In a cecal ligation and puncture-induced sepsis model, we observed increased lipid biosynthesis and significantly elevated SREBF1 expression in spleen DCs. Increased SREBF1 expression suppressed the expression of costimulatory molecules (e.g., CD40, CD80, and CD86) and MHC II, reduced the secretion of inflammatory cytokines (e.g., TNFα, IL-1β, IL-6, and IL-12), impaired CD4+ T cell activation, and promoted apoptosis. Mechanistically, SREBF1 activation enhanced lipid biosynthesis in DCs, which triggered endoplasmic reticulum (ER) stress, as evidenced by increased PERK phosphorylation, eIF2α activation, and subsequent ATF4/CHOP induction. SREBF1 silencing attenuated the lipid-induced ER stress and restored DC function, whereas tunicamycin treatment partially reversed these protective effects.

CONCLUSIONS

Our study identifies SREBF1 as a central regulator of sepsis-induced DC immunoparalysis by coupling lipid metabolic reprogramming to ER stress activation. Targeting this SREBF1-lipid-ER stress axis represents a novel strategy to reverse immunosuppression in septic patients.