M1 Macrophage Polarization Is Dependent on TRPC1-Mediated Calcium Entry

Macrophage plasticity is essential for innate immunity, but in-depth signaling mechanism(s) regulating their functional phenotypes are ill-defined. Here we report that interferon (IFN) γ priming of naive macrophages induces store-mediated Ca(2+) entry and inhibition of Ca(2+) entry impairs polarization to M1 inflammatory phenotype. In vitro and in vivo functional analyses revealed ORAI1 to be a primary contributor to basal Ca(2+) influx in macrophages, whereas IFNγ-induced Ca(2+) influx was mediated by TRPC1. Deficiency of TRPC1 displayed abrogated IFNγ-induced M1 inflammatory mediators in macrophages. In a preclinical model of peritonitis by Klebsiella pneumoniae infection, macrophages showed increased Ca(2+) influx, which was TRPC1 dependent. Macrophages from infected TRPC1(−/−) mice showed inhibited expression of M1-associated signature molecules. Furthermore, in human patients with systemic inflammatory response syndrome, the level of TRPC1 expression in circulating macrophages directly correlated with M1 inflammatory mediators. Overall, TRPC1-mediated Ca(2+) influx is essential for the induction/shaping of macrophage polarization to M1 inflammatory phenotype.