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

Hydrogen sulfide (H₂S) 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 H₂S on T cells, its impact on B cells has yet to be elucidated.

We used sodium hydrosulfide (NaHS) as an exogenous donor for H₂S. 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 H₂S-induced B_regs to mice with LPS-induced acute lung injury.

Both exogenous and endogenous H₂S 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 H₂S functionally suppressed neutrophils and CD4 T cells. H₂S-induced B_regs not only induced neutrophil apoptosis and suppressed neutrophil ROS but also inhibited CD4 T cell proliferation and pro-inflammatory cytokine production. H₂S enhanced PI3K/Akt/mTORC1 signaling pathway and glycolysis during LPS stimulation, which partially mediated IL-10 production and PD-L1 expression. Moreover, H₂S 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 H₂S-induced B_regs, which were confirmed with mitochondrial-specific redox regulators. In LPS-induced acute lung injury model, adoptive transfer of H₂S-induced B_regs was able to protect tissue damage and alleviate lung inflammation by decreasing pro-inflammatory cytokines and increasing neutrophil apoptosis.

This study reveals that H₂S shifts B cells to have regulatory phenotypes via shifting metabolic pathway and enhancing mitochondrial expenditure. H₂S can serve as one of the inducers and environmental signals for B_regs to resolve inflammation via signaling and metabolic pathways in B cells.