Calcium-sensitive receptors-mediated macrophage polarization via the PLC-Ca 2+ and cAMP-NF-κB-NLRP3 inflammasome signalling pathways impact cardiac fibroblast activation through paracrine effects

The cardiac inflammatory response, characterized by immune cell infiltration, is involved in developing myocardial fibrosis during hypertension. Although calcium-sensitive receptor (CaSR) regulates inflammatory response, the specific mechanism remains unclear. To determine the role of CaSR in regulating hypertensive macrophage polarization, CaSR agonists/inhibitors were intraperitoneally injected into16-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, followed by examining the macrophage polarization markers and cardiac collagen deposition in the rat hearts. The study used the RAW264.7 macrophage cell line and the mouse myocardial fibroblast cell line to investigate the signaling pathway of CaSR regulating macrophage polarization and the effect of macrophage polarization on myocardial fibroblasts. We also detected the changes in macrophage polarization markers and Ca /cAMP/NF-κB/NLRP3 inflammasome signaling molecules, myocardial fibroblast proliferation, and transdifferentiation markers with the intervention of related drugs. CaSR reduces M1-type polarization and enhances M2-type polarization of SHR myocardial tissue macrophages by reducing NLRP3 inflammasome activation, alleviating hypertensive myocardial fibrosis. In isolated macrophages, CaSR activates NLRP3 inflammasome via the PLC/Ca and cAMP/NF-κB signaling pathways, which subsequently promotes M1-type polarization, reduces M2-type polarization in macrophages, and promotes activation of cardiac fibroblasts via paracrine effects.