Activation in M1 but not M2 Macrophages Contributes to Cardiac Remodeling after Myocardial Infarction in Rats: a Critical Role of the Calcium Sensing Receptor/NRLP3 Inflammasome

Aims: Macrophage (M Phi) infiltration during myocardial infarction (MI) amplifies cardiac inflammation and remodeling. We investigated whether activation of the NRLP3 inflammasome by a calcium sensing receptor (CaSR) in MO subsets contributes to cardiac remodeling following MI. Methods and Results: Infiltrated MO exhibited biphasic activation after MI; MINK) peaked at MI 3d and decreased until MI 14d, whereas M2M Phi peaked at MI 7d and decreased at MI 14d as shown via immunohistochemistry. IL-1 beta, co-infiltrated with both M1M Phi and M2M Phi; IL-1 beta exhibited the same infiltrating tendency as M1M Phi, which was detected by immunohistochemistry. Increasing ventricular fibrosis was confirmed by Masson staining. CaSR and NLRP3 inflammasome in the MI group were upregulated in MO subsets in myocardium and peritoneal M Phi (p-M Phi) compared with the sham groups which were detected by immunofluorescence and western blotting. CaSR-activated NLRP3 inflammasome played a role in M1M Phi via PLC-1P(3) but did not play a role in M2M Phi which were polarized by the THP-1 as shown by western blotting and intracellular calcium measurement. CaSR/NLRP3 inflammasome activation in M1M Phi led to the following effects: upregulated alpha-sma, MMP-2 and MMP-9, and collagen secretion; and downregulated TIMP-2 in cardiac fibroblasts via IL-43-IL-1RI, which was detected by coculturing M1M Phi and cardiac fibroblasts. Conclusions: We suggest that the CaSR/NLRP3 inflammasome plays an essential role via the PLC-IP3 pathway in M1M Phi to promote cardiac remodeling post-MI in rats, including accelerated cardiac fibroblast phenotypic transversion, increased collagen and extracellular matrix (ECM) secretion; however, the CaSR/NLRP3inflammasome does not play a role in this process in M2M Phi. Copyright (C) 2015 S. Karger AG, Basel