Apoptosis releases hydrogen sulfide to inhibit Th17 cell differentiation

Abstract

Over 50 billion cells undergo apoptosis each day in an adult human to maintain immune homeostasis. Hydrogen sulfide (H₂S) is also required to safeguard the function of immune response. However, it is unknown whether apoptosis regulates H₂S production. Here, we show that apoptosis-deficient MRL/lpr (B6.MRL-Faslpr/J) and Bim^-/- (B6.129S1-Bcl2l11tm1.1Ast/J) mice exhibit significantly reduced H₂S levels along with aberrant differentiation of Th17 cells, which can be rescued by the additional H₂S. Moreover, apoptotic cells and vesicles (apoVs) express key H₂S-generating enzymes and generate a significant amount of H₂S, indicating that apoptotic metabolism is an important source of H₂S. Mechanistically, H₂S sulfhydrates selenoprotein F (Sep15) to promote signal transducer and activator of transcription 1 (STAT1) phosphorylation and suppress STAT3 phosphorylation, leading to the inhibition of Th17 cell differentiation. Taken together, this study reveals a previously unknown role of apoptosis in maintaining H₂S homeostasis and the unique role of H₂S in regulating Th17 cell differentiation via sulfhydration of Sep15^C38.

Keywords: SLE; Th17 cells; apoVs; apoptosis; apoptotic vesicles; hydrogen sulfide; systemic lupus erythematosus.