Hydrogen sulfide induces regulatory B cells via glycolysis and mitochondrial ROS, attenuating LPS-induced lung injury.

BACKGROUND: Hydrogen sulfide (H(2)S) is a gasotransmitter found in the human body that plays a crucial role in maintaining homeostasis of various biological systems, including the immune system. While prior studies have explored the effects of H(2)S on T cells, its impact on B cells has yet to be elucidated. METHODS: We used sodium hydrosulfide (NaHS) as an exogenous donor for H(2)S. LPS was used to activate B cells and promote their differentiation into plasma cells or regulatory B cells (B(regs)). B(regs) phenotypes were analyzed by flow cytometry and ELISA, and their immunosuppressive functions on neutrophils and CD4 T cells were assessed by co-culturing them with B cells. To investigate the therapeutic effect of B cells on acute lung injury, we adoptively transferred H(2)S-induced B(regs) to mice with LPS-induced acute lung injury. RESULTS: Both exogenous and endogenous H(2)S induced regulatory phenotypes of B cells including IL-10 production and programmed cell death ligand-1 (PD-L1) expression. B(regs) induced by LPS and exogenous H(2)S functionally suppressed neutrophils and CD4 T cells. H(2)S-induced B(regs) not only induced neutrophil apoptosis and suppressed neutrophil ROS but also inhibited CD4 T cell proliferation and pro-inflammatory cytokine production. H(2)S enhanced PI3K/Akt/mTORC1 signaling pathway and glycolysis during LPS stimulation, which partially mediated IL-10 production and PD-L1 expression. Moreover, H(2)S donor administration activated mitochondrial electron transport chain usage, resulting in increased mitochondrial oxygen consumption. Change of mitochondrial redox state contributed to the regulatory phenotypes of H(2)S-induced B(regs), which were confirmed with mitochondrial-specific redox regulators. In LPS-induced acute lung injury model, adoptive transfer of H(2)S-induced B(regs) was able to protect tissue damage and alleviate lung inflammation by decreasing pro-inflammatory cytokines and increasing neutrophil apoptosis. CONCLUSIONS: This study reveals that H(2)S shifts B cells to have regulatory phenotypes via shifting metabolic pathway and enhancing mitochondrial expenditure. H(2)S can serve as one of the inducers and environmental signals for B(regs) to resolve inflammation via signaling and metabolic pathways in B cells.