LUCAT1/PTBP1/HIF-1α feedback loop promotes T cell over-differentiation and Th1/Th2-skewed immune imbalance in sepsis via glucose metabolism.

BACKGROUND

Sepsis, a life-threatening clinical syndrome linked to Th1/Th2-skewed immune imbalance, involves glucose metabolism reprogramming. Because women remain under-represented in many sepsis studies and sex-specific host responses may influence disease trajectories, this study aims to delineate the mechanism of lncRNA LUCAT1 in Th1/Th2-skewed immune imbalance during sepsis in women via glucose metabolism reprogramming.

METHOD: Peripheral blood from female patients with post-traumatic sepsis was examined for LUCAT1, PTBP1, and HIF1A expression. Flow cytometry quantified CD4+/CD8+ and Th1/Th2 ratios. Starbase analysis predicted regulatory relationships among LUCAT1, PTBP1, and HIF1A. These predictions were validated through dual luciferase reporter gene assays, ChIP, RIP, and actinomycin D assay. Primary human CD4+ T cells were cultured and activated with anti-CD3/CD28 (αCD3/CD28), treated with 2-DG (glycolysis inhibitor), and assayed for inflammatory factors (IL-1β, IL-6 and TNF-α), glycolytic genes (GLUT1, HK2, LDHA), glycolytic indexes (glucose uptake, lactate generation, ATP, ECAR and OCR) and Th1/Th2 differentiation.

RESULT: Post-traumatic sepsis patients display elevated LUCAT1, PTBP1, and HIF1-A in peripheral blood lymphocytes alongside decreased CD4+/CD8+ and elevated Th1/Th2. HIF-1α promoted LUCAT1 transcription. LUCAT1, acting as a scaffold, may facilitate PTBP1's regulation on HIF1A mRNA stability. Silencing LUCAT1 inhibited and overexpressing LUCAT1 increased inflammatory mediator secretions, glycolysis, Th1/Th2 ratio in αCD3/CD28-induced Primary human CD4+ T cells. 2-DG partially reversed the effects of LUCAT1 overexpression, whereas HIF1A overexpression countered (rescued) the effects of LUCAT1 silencing.

CONCLUSION

LUCAT1/PTBP1/HIF-1α positive feedback loop drives excessive T cell differentiation and Th1/Th2-skewed immune imbalance in sepsis via glucose metabolic reprogramming, which may contribute to disease progression.