Calcium sensing receptor activation in THP-1 macrophages triggers NLRP3 inflammasome and human preadipose cell inflammation.

Affiliation

Institute of Nutrition and Food Technology, University of Chile, El Líbano 5524, Macul, Casilla 138-11, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, 8380492, Chile; Center for Exercise, Metabolism and Cancer (CEMC), Facultad de Medicina, Universidad de Chile, Santiago, 8380492, Chile. Electronic address: [Email]

Abstract

Excess adipose tissue (AT) associates with inflammation and obesity-related diseases. We studied whether calcium-sensing receptor (CaSR)-mediated NLRP3 inflammasome activation in THP-1 macrophages elevates inflammation in LS14 preadipocytes, modeling deleterious AT cell crosstalk. THP-1 macrophages exposed to cinacalcet (CaSR activator, 2 μM, 4 h) showed elevated proinflammatory marker and NLRP3 inflammasome mRNA, pro-IL-1β protein and caspase-1 activity, whereas preincubation with CaSR negative modulators prevented these effects. The key NLRP3 inflammasome component ASC was silenced (siRNA) in THP-1 cells, and inflammasome activation was evaluated (qPCR, Western blot, caspase-1 activity) or they were further cultured to obtain conditioned medium (CoM). Exposure of LS14 preadipocytes to CoM from cinacalcet-treated THP-1 elevated LS14 proinflammatory cytokine expression, which was abrogated by THP-1 inflammasome silencing. Thus, CaSR activation elevates THP-1-induced inflammation in LS14 preadipocytes, via macrophage NLRP3 inflammasome activation. Modulating CaSR activation may prevent deleterious proinflammatory cell crosstalk in AT, a promising approach in obesity-related metabolic disorders.

Keywords

Calcium sensing receptor,Crosstalk,Macrophages,NLRP3 inflammasome,Preadipocytes,

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