Calcium-sensing receptor activates the NLRP3 inflammasome in LS14 preadipocytes mediated by ERK1/2 signaling

The study of the mechanisms that trigger inflammation in adipose tissue is key to understanding and preventing the cardiometabolic consequences of obesity. We have proposed a model where activation of the G protein-coupled calcium sensing receptor (CaSR) leads to inflammation and dysfunction in adipose cells. Upon activation, CaSR can mediate the expression and secretion of proinflammatory factors in human preadipocytes, adipocytes, and adipose tissue explants. One possible pathway involved in CaSR-induced inflammation is the activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome, that promotes maturation and secretion of interleukin (IL)-1. The present work aimed to study whether CaSR mediates the activation of NLRP3 inflammasome in the human adipose cell model LS14. We assessed NLRP3 inflammasome priming and assembly after cinacalcet-induced CaSR activation and evaluated if this activation is mediated by downstream ERK1/2 signaling in LS14 preadipocytes. Exposure to 2M cinacalcet elevated mRNA expression of NLRP3, CASP-1, and IL-1, as well as an increase in pro-IL-1 protein. In addition, CaSR activation triggered NLRP3 inflammasome assembly, as evidenced by a 25% increase in caspase-1 activity and 63% IL-1 secretion. CaSR silencing (siRNA) abolished the effect. Upstream ERK pathway inhibition decreased cinacalcet-dependent activation of NLRP3 inflammasome. We propose CaSR-dependent NLRP3 inflammasome activation in preadipocytes through ERK signaling as a novel mechanism for the development of adipose dysfunction, that may favor the cardiovascular and metabolic consequences of obesity. To the best of our knowledge, this is the first report linking the inflammatory effect of CaSR to NLRP3 inflammasome induction in adipose cells.

Fondo Nacional de Desarrollo Cientifico y Tecnologico (Chile) 1150651 Comision Nacional de Investigacion Cientifica y Tecnologica (Chile) 2114028