Erschienen:
Springer Science and Business Media LLC, 2022
Erschienen in:
International Journal of Obesity, 46 (2022) 10, Seite 1883-1891
Sprache:
Englisch
DOI:
10.1038/s41366-022-01135-x
ISSN:
0307-0565;
1476-5497
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Objective</jats:title>
<jats:p>Obesity is complicated by inflammatory activation of the innate immune system. Stimulation of the calcium-sensing receptor (CaSR) by extra-cellular calcium ions ([Ca<jats:sup>2+</jats:sup>]<jats:sub>ex</jats:sub>) 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<jats:sup>2+</jats:sup>]<jats:sub>ex</jats:sub>-induced, CaSR mediated IL-1β release by macrophages in obesity.</jats:p>
</jats:sec><jats:sec>
<jats:title>Methods</jats:title>
<jats:p>[Ca<jats:sup>2+</jats:sup>]<jats:sub>ex</jats:sub>-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<jats:sup>2+</jats:sup>]<jats:sub>ex</jats:sub>, and IL-1β release, as well as expression of NLRP3 inflammasome and cytokine genes, was determined.</jats:p>
</jats:sec><jats:sec>
<jats:title>Results</jats:title>
<jats:p>Both MDM and AT readily responded with concentration-dependent IL-1β release already at low, near physiological concentrations to addition of [Ca<jats:sup>2+</jats:sup>]<jats:sub>ex</jats:sub>, which was more than 80 fold higher than the LPS-induced effect. IL-1β levels induced by [Ca<jats:sup>2+</jats:sup>]<jats:sub>ex</jats:sub> 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.</jats:p>
</jats:sec><jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>Obesity renders macrophages more susceptible to [Ca<jats:sup>2+</jats:sup>]<jats:sub>ex</jats:sub>-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.</jats:p>
</jats:sec>