International journal of obesity (2005) · 2022
Macrophages in obesity are characterised by increased IL-1β response to calcium-sensing receptor signals.
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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
Аннотация
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-1β release by macrophages in obesity.
METHODS: [Ca2+]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 [Ca2+]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 [Ca2+]ex, which was more than 80 fold higher than the LPS-induced effect. IL-1β 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-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.
METHODS: [Ca2+]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 [Ca2+]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 [Ca2+]ex, which was more than 80 fold higher than the LPS-induced effect. IL-1β 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-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.