Hydrogen sulfide derived from apoptotic cells supports immune homeostasis

In the latest issue of Cell Metabolism, Songtao Shi's group reveal that apoptosis is responsible for maintaining the homeostasis of hydrogen sulfide (H2S) in the body. It does so by restraining the abnormal activation of Th17 cell via sulfhydration of selenoprotein F (Sep15) [1].

Apoptosis is a type of programmed cell death, with approximately 50–70 billion cells undergoing apoptosis each day [2]. In recent years, several experimental results have clarified that apoptosis is related to autoimmune diseases, such as systemic lupus erythematosus (SLE) [3]. Apoptotic vesicles (apoVs), released by apoptotic cells, contain many components, including DNA, RNA, and proteins, which play a role in immune modulation and the promotion of cell regeneration [4]. Additionally, apoVs can also transmit metabolites to target cells and organs [5].

Hydrogen sulfide (H2S), considered a gasotransmitter, has the ability to freely penetrate cell membranes and signal specific cellular targets [6]. H2S is a natural buffer for the immune system, and its deficiency can lead to significant immune disorders [7]. H2S is generated within apoptotic cells by H2S-generating enzymes and exerts its physiological function through sulfhydration modification, a novel post-translational modification involved in multiple pathophysiological processes, including cell survival/death, differentiation, proliferation/hypertrophy, lipid metabolism, and others [8]. In 2015, Songtao Shi's team published a paper in the journal Immunity, revealing the importance of endogenous H2S in maintaining immune balance and its connection to immune diseases related to T cells [9]. Given that both apoptosis defects and H2S deficiency can cause severe immune disorders, it suggests a possible link between the apoptosis process and the production of endogenous H2S. More recently, Songtao Shi's team discovered that the decrease in H2S levels is associated with apoptosis defect. Additionally, H2S inhibits Th17 cell activation by sulfhydrating selenoprotein F at the C38 site (Sep15^C38) [1].

Cell apoptosis defects are closely linked to SLE, characterized by a notable increase in the number of Th17 cells in circulation and tissues. The infiltration of Th17 cells triggers tissue inflammation and organ damage. Inhibiting the differentiation of Th17 cells in SLE patients is a prospective approach to alleviate inflammatory damage and slow down disease progression. In their study, Shi and colleagues propose a novel concept called "apoptotic gas" production. They found that cell apoptosis serves as a significant source of endogenous H2S in the body. H2S derived from apoptotic cells can hinder the abnormal differentiation of Th17 cells by modifying key proteins through sulfhydration. Additionally, they introduce a new form of "apoptotic inheritance" for the first time. It is discovered that apoVs possess the capability to inherit the cell's ability to generate H2S. Notably, apoVs may offer another practicable way to treat SLE and provide a new perspective on clinical treatments. This research is promising and may have significant implications in clinical medicine (Fig. 1).

Fig. 1.

H2S, derived from apoptotic cell, supports immune homeostasis. Apoptotic cells are considered vital reservoirs that produce endogenous H2S. This molecule exerts inhibitory effects on aberrant Th17 cell differentiation through sulfhydration, thereby mitigating the risk of systemic lupus erythematosus (SLE) development. By Figdraw (http://www.figdraw.com).

CRediT authorship contribution statement

Ying Xu: Conceptualization, Writing – original draft. Suzhen Chen: Conceptualization, Supervision, Writing – original draft, Writing – review & editing. Junli Liu: Conceptualization, Supervision, Validation, Writing – original draft, Writing – review & editing.