Background 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. Methods 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 (Bregs). Bregs 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 Bregs to mice with LPS-induced acute lung injury. Results Both exogenous and endogenous H2S induced regulatory phenotypes of B cells including IL-10 production and programmed cell death ligand-1 (PD-L1) expression. Bregs induced by LPS and exogenous H2S functionally suppressed neutrophils and CD4 T cells. H2S-induced Bregs 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 Bregs, which were confirmed with mitochondrial-specific redox regulators. In LPS-induced acute lung injury model, adoptive transfer of H2S-induced Bregs was able to protect tissue damage and alleviate lung inflammation by decreasing pro-inflammatory cytokines and increasing neutrophil apoptosis. Conclusions 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 Bregs to resolve inflammation via signaling and metabolic pathways in B cells.

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

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2025年10月21日

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Yu Sun Jeong,
Byunghyun Park,
Mingyu Lee,
Ji Cheol Kim,
Ji Ye Park,
Brian A. Zabel,
Yoe-Sik Bae

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.