H2S serves as the immunoregulatory essence of apoptotic cell death

Abstract

Apoptosis supports tissue homeostasis and prevents immune disorders by removing damaged and functionally aberrant cells. Here, Ou et al. utilized genetic, pharmacological, and proteomic approaches focused on sulfur amino acid catabolism to discover that hydrogen sulfide (H₂S) release during apoptosis suppresses Th17 cell differentiation, thus providing therapeutic targets for autoimmune diseases.

Figure 1:. Apoptosis, endogenous hydrogen sulfide (H₂S) production, and sulfhydration signaling drive immune homeostasis by suppressing aberrant Th17 cell differentiation.

Apoptotic signals including those initiated by staurosporine (STS) but perturbed by genetic mutations MRL/lpr and Bim−/− or the caspase inhibitor drug Z-VAD drive enzymatic H₂S production via the catabolism of cysteine in the resultant apoptotic cells and vesicles. Diminished H₂S production via knocking out the pyridoxal phosphate (PLP)-dependent H₂S generating enzymes cystathionine γ-lyase (CSE) or cystathionine β-synthase (CBS) or treatment with their pharmacological inhibitors propargylglycine (PAG) or hydroxylamine hydrochloride (HA) limits sulfhydration (SSH) of selenoprotein F (Sep15), which can be rescued by exposure to the exogenous H₂S producer sodium hydrosulfide (NaHS). Sulfhydrated Sep15 stimulates nuclear translation and phosphorylation (P) of signal transducer and activator of transcription 1 (STAT1) limiting aberrant Th17 cell differentiation and downstream pathogenesis in immune-related diseases such as systemic lupus erythematosus. Green arrows indicate stimulation, while red crosses indicate inhibition. Figure made using BioRender.