期刊
INTERNATIONAL JOURNAL OF OBESITY
卷 46, 期 10, 页码 1883-1891出版社
SPRINGERNATURE
DOI: 10.1038/s41366-022-01135-x
关键词
-
资金
- Federal Ministry of Education and Research (BMBF), Germany [FKZ: 01EO1001]
Inflammatory activation of the innate immune system is complicated in obesity. This study investigates the role of calcium-sensing receptor (CaSR) in the activation of adipose tissue (AT) in obesity. The results suggest that CaSR-mediated signaling may contribute to the innate immune activation and inflammation in obesity.
Objective Obesity is complicated by inflammatory activation of the innate immune system. Stimulation of the calcium-sensing receptor (CaSR) by extra-cellular calcium ions ([Ca2+](ex)) can trigger NLRP3 inflammasome activation and inflammation. We hypothesised, that this mechanism might contribute to the activation of adipose tissue (AT) in obesity, and investigated [Ca2+](ex)-induced, CaSR mediated IL-1 beta release by macrophages in obesity. Methods [Ca2+](ex)-induced IL-1 beta release was investigated in monocyte-derived macrophages (MDM) generated from peripheral blood of patients with obesity and from normal-weight controls. Visceral and subcutaneous AT biosamples were stimulated with [Ca2+](ex), and IL-1 beta release, as well as expression of NLRP3 inflammasome and cytokine genes, was determined. Results Both MDM and AT readily responded with concentration-dependent IL-1 beta release already at low, near physiological concentrations to addition of [Ca2+](ex), which was more than 80 fold higher than the LPS-induced effect. IL-1 beta levels induced by [Ca2+](ex) were significantly higher not only in MDM from patients with obesity compared to controls, but also in visceral versus subcutaneous AT. This fat-depot difference was also reflected by mRNA expression levels of inflammasome and cytokine genes. Conclusions Obesity renders macrophages more susceptible to [Ca2+](ex)-induced IL-1 beta release and pyroptosis. Increased susceptibility was independent of the response to LPS and circulating CRP arguing against mere pro-inflammatory pre-activation of monocytes. Instead, we propose that CaSR mediated signalling is relevant for the deleterious innate immune activation in obesity.
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