Depletion of H ₂ S during obesity enhances store-operated Ca ²⁺ entry in adipose tissue macrophages to increase cytokine production

Abstract

The increased production of proinflammatory cytokines by adipose tissue macrophages (ATMs) contributes to chronic, low-level inflammation during obesity. We found that obesity in mice reduced the bioavailability of the gaseous signaling molecule hydrogen sulfide (H2S). Steady-state, intracellular concentrations of H2S were lower in ATMs isolated from mice with diet-induced obesity than in ATMs from lean mice. In addition, the intracellular concentration of H2S in the macrophage cell line RAW264.7 was reduced during an acute inflammatory response evoked by the microbial product lipopolysaccharide (LPS). Reduced intracellular concentrations of H2S led to increased Ca2+ influx through the store-operated Ca2+ entry (SOCE) pathway, which was prevented by the exogenous H2S donor GYY4137. Furthermore, GYY4137 inhibited the Orai3 channel, a key component of the SOCE machinery. The enhanced production of proinflammatory cytokines by RAW264.7 cells and ATMs from obese mice was reduced by exogenous H2S or by inhibition of SOCE. Together, these data suggest that the depletion of macrophage H2S that occurs during acute (LPS-induced) or chronic (obesity) inflammation increases SOCE through disinhibition of Orai3 and promotes the production of proinflammatory cytokines.

Exogenous hydrogen sulfide inhibits oral mucosal wound‐induced macrophage activation via the NF‐κB pathway

“…However, prolonged inflammatory reactions may not only retard the wound‐healing process but also favor tissue fibrosis, which reduces the possibility of true regeneration (Arancibia et al., ). Another study showed that the bioavailability of H 2 S was reduced in obese mice with increased pro‐inflammatory cytokine levels, and the increased pro‐inflammatory cytokine production was prevented by the exogenous H 2 S donor GYY4137 (Velmurugan et al., ). These results collectively suggest that the inflammatory microenvironment can inhibit the production of endogenous H 2 S, and in the normal wound‐healing processes, the supplemental H 2 S might delay the wound‐healing quality.…”

Hydrogen Sulfide in the Adipose Tissue—Physiology, Pathology and a Target for Pharmacotherapy

“…Increase in M 1 markers such as IL-6, IL-1β, and inducible nitric oxide synthase and decrease in M 2 markers such as arginase-2 or mannose receptor C type 1 (MRC1) in obese mice are reversed by GYY4137 as well as SOCE inhibitors. Overall, these results indicate that H 2 S deficiency contributes to SOCE activation and proinflammatory phenotype switch of adipose tissue macrophages associated with obesity [ 77 ].…”

Endogenous Hydrogen Sulfide Ameliorates NOX4 Induced Oxidative Stress in LPS-Stimulated Macrophages and Mice

“…It has been reported that the increased H 2 S circulation detected in the burn injury [36] and its levels correlated with inflammatory and clinical indices in rheumatoid arthritis patients [37]. Moreover, multiple lines of studies, in multiple experimental models, showing that therapeutic elevation of H 2 S concentrations or H 2 S donors can exert anti-inflammation and decrease the mortality caused by endotoxemia [38][39][40]. We found that CSE expression was significantly increased in LPS-induced macrophage, which were accompanied by increased inflammatory mediators and inflammatory cytokines production.…”