Macrophages in obesity are characterised by increased IL-1β response to calcium-sensing receptor signals

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.

Automated summary

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.