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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...

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Published in:International Journal of Obesity 2022-10, Vol.46 (10), p.1883-1891
Main Authors: Thrum, Stephan, Sommer, Miriam, Raulien, Nora, Gericke, Martin, Massier, Lucas, Kovacs, Peter, Krasselt, Marco, Landgraf, Kathrin, Körner, Antje, Dietrich, Arne, Blüher, Matthias, Rossol, Manuela, Wagner, Ulf
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Language:English
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Summary: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.
ISSN:0307-0565
1476-5497
DOI:10.1038/s41366-022-01135-x