HIF-1α-driven lactate from mesenchymal stem/stromal cells reprograms monocyte metabolism and suppresses autoimmune...

Metabolic reprogramming of immune cells is emerging as a therapeutic strategy for autoimmune diseases. Here, we identify mesenchymal stem/stromal cell (MSC)-derived lactate as a signaling metabolite that reprograms monocyte metabolism and differentiation. GM-CSF enhanced glycolytic activity in bone marrow cells and expanded pro-inflammatory monocytes, whereas pharmacologic inhibition of glycolysis with 2-deoxy-D-glucose reversed these effects. MSC coculture suppressed glycolytic activation and redirected monocyte differentiation toward an immunosuppressive phenotype. MSCs produced lactate in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner, and blocking lactate production through oxamate treatment or HIF1A knockdown attenuated the effects of MSCs on differentiating monocytes, whereas exogenous lactate recapitulated them. In experimental autoimmune uveoretinitis, intravenous administration of MSCs ameliorated the disease, but oxamate-pretreated or HIF1A-knockdown MSCs exhibited reduced efficacy. The HIF-1α-lactate axis may therefore represent a targetable pathway for optimizing MSC-based therapies and for developing lactate-centered interventions in autoimmune diseases.