Chauhan Arun, Sun Yuyang, Sukumaran Pramod, Quenum Zangbede Fredice O, Jondle Christopher N, Sharma Atul, Evans Dustin L, Chauhan Pooja, Szlabick Randolph E, Aaland Mary O, Birnbaumer Lutz, Sharma Jyotika, Singh Brij B, Mishra Bibhuti B
Department of Biomedical Sciences and Department of Surgery, School of Medicine & Health Sciences, The University of North Dakota, 1301 N Columbia Road, Grand Forks, ND 58202, USA.
Neurobiology Laboratory, NIHES, NIH, 111 TW Alexander Dr., Research Triangle Park, Durham, NC 27709, USA; School of Medical Sciences, Catholic University of Argentina, Institute of Biomedical Research (BIOMED UCA-CONICET), Av. Alicia Moreau de Justo 1300, Edificio San Jose Piso 3, Buenos Aires C1107AAZ, Argentina.
iScience. 2018 Oct 26;8:85-102. doi: 10.1016/j.isci.2018.09.014. Epub 2018 Sep 20.
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.
巨噬细胞可塑性对于固有免疫至关重要，但调节其功能表型的深入信号机制尚不明确。在此我们报告，天然巨噬细胞经干扰素（IFN）γ预处理可诱导钙库调控的钙离子内流，而抑制钙离子内流会损害其向M1炎症表型的极化。体外和体内功能分析表明，ORAI1是巨噬细胞基础钙离子内流的主要贡献者，而IFNγ诱导的钙离子内流由TRPC1介导。TRPC1缺陷导致巨噬细胞中IFNγ诱导的M1炎症介质缺失。在肺炎克雷伯菌感染引起的腹膜炎临床前模型中，巨噬细胞的钙离子内流增加，且依赖于TRPC1。感染TRPC1基因敲除小鼠的巨噬细胞中，M1相关标志性分子的表达受到抑制。此外，在患有全身炎症反应综合征的人类患者中，循环巨噬细胞中TRPC1的表达水平与M1炎症介质直接相关。总体而言，TRPC1介导的钙离子内流对于巨噬细胞向M1炎症表型的诱导/形成至关重要。
