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 ([Ca(2+)](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 [Ca(2+)](ex)-induced, CaSR mediated IL-1β release by macrophages in obesity. METHODS: [Ca(2+)](ex)-induced IL-1β 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 [Ca(2+)](ex), and IL-1β release, as well as expression of NLRP3 inflammasome and cytokine genes, was determined. RESULTS: Both MDM and AT readily responded with concentration-dependent IL-1β release already at low, near physiological concentrations to addition of [Ca(2+)](ex), which was more than 80 fold higher than the LPS-induced effect. IL-1β levels induced by [Ca(2+)](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 [Ca(2+)](ex)-induced IL-1β 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.