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 entry and inhibition of Ca entry impairs polarization to M1 inflammatory phenotype. In vitro and in vivo functional analyses revealed ORAI1 to be a primary contributor to basal Ca influx in macrophages, whereas IFNγ-induced Ca 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 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 influx is essential for the induction/shaping of macrophage polarization to M1 inflammatory phenotype.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174824 | PMC |
| http://dx.doi.org/10.1016/j.isci.2018.09.014 | DOI Listing |
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