Research ArticleInflammation

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

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Science Signaling  15 Dec 2015:
Vol. 8, Issue 407, pp. ra128
DOI: 10.1126/scisignal.aac7135

Limiting inflammation in obesity

Obese individuals have increased amounts of inflammatory cytokines in the circulation, which are produced by adipose tissue macrophages (ATMs). Velmurugan et al. found that ATMs from obese mice had decreased amounts of the gaseous signaling molecule hydrogen sulfide (H2S) than did ATMs from lean mice. ATMs from obese mice had enhanced store-operated calcium entry and produced more proinflammatory cytokines. Treatment of macrophages with the bacterial product lipopolysaccharide also decreased H2S concentrations and increased inflammatory cytokine production. Knockdown experiments showed that H2S inhibited the channel protein Orai3 to reduce calcium entry into macrophages. Together, these data suggest that inflammatory stimuli lead to the depletion of H2S in adipose tissue, which exacerbates inflammatory responses by resident ATMs.


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.

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