M1 Macrophage Polarization Is Dependent on TRPC1-Mediated Calcium Entry

Authors: Arun Chauhan, Yuyang Sun, Pramod Sukumaran, Fredice O. Quenum Zangbede, C. N. Jondle, Atul Sharma, Dustin L. Evans, Pooja Chauhan, Randolph E. Szlabick, Mary O. Aaland, Lutz Birnbaumer, Jyotika Sharma, Brij B. Singh, Bibhuti B. Mishra - iScience 2018 cited by 89

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.