Journal
ISCIENCE
Volume 8, Issue -, Pages 85-+Publisher
CELL PRESS
DOI: 10.1016/j.isci.2018.09.014
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Funding
- National Institutes of Health (United States) [R21DE024300, P20GM113123, R21AI107457, R01AI121804, R01DE017102, Z01-ES-101684]
- National Institutes of Health [5P20GM113123, 5P20GM103442]
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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) gamma priming of naive macrophages induces store-mediated Ca2+ entry and inhibition of Ca2+ entry impairs polarization to M1 inflammatory phenotype. In vitro and in vivo functional analyses revealed ORAI1 to be a primary contributor to basal Ca2+ influx in macrophages, whereas IFN gamma-induced Ca2+ influx was mediated by TRPC1. Deficiency of TRPC1 displayed abrogated IFN gamma-induced M1 inflammatory mediators in macrophages. In a preclinical model of peritonitis by Kiebsiella pneumoniae infection, macrophages showed increased Ca2+ 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 Ca2+ influx is essential for the induction/shaping of macrophage polarization to M1 inflammatory phenotype.
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