Depletion of H₂S during obesity enhances store-operated Ca²⁺ entry in adipose tissue macrophages to increase cytokine production

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. Inaddition, the intracellular concentration of H₂S inthe 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.