Nascimento Da Conceicao Viviane, Sun Yuyang, Ramachandran Karthik, Chauhan Arun, Raveendran Amritha, Venkatesan Manigandan, DeKumar Bony, Maity Soumya, Vishnu Neelanjan, Kotsakis George A, Worley Paul F, Gill Donald L, Mishra Bibhuti B, Madesh Muniswamy, Singh Brij B
Department of Periodontics, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
Department of Medicine, Cardiology Division, Center for Precision Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
iScience. 2021 Oct 23;24(11):103339. doi: 10.1016/j.isci.2021.103339. eCollection 2021 Nov 19.
Transformation of naive macrophages into classically (M1) or alternatively (M2) activated macrophages regulates the inflammatory response. Here, we identified that distinct Ca entry channels determine the IFNγ-induced M1 or IL-4-induced M2 transition. Naive or M2 macrophages exhibit a robust Ca entry that was dependent on Orai1 channels, whereas the M1 phenotype showed a non-selective TRPC1 current. Blockade of Ca entry suppresses pNF-κB/pJNK/STAT1 or STAT6 signaling events and consequently lowers cytokine production that is essential for M1 or M2 functions. Of importance, LPS stimulation shifted M2 cells from Orai1 toward TRPC1-mediated Ca entry and TRPC1 mice exhibited transcriptional changes that suppress pro-inflammatory cytokines. In contrast, Orai1 macrophages showed a decrease in anti-inflammatory cytokines and exhibited a suppression of mitochondrial oxygen consumption rate and inhibited mitochondrial shape transition specifically in the M2 cells. Finally, alterations in TRPC1 or Orai1 expression determine macrophage polarization suggesting a distinct role of Ca channels in modulating macrophage transformation.
幼稚巨噬细胞向经典激活（M1）或交替激活（M2）巨噬细胞的转变调节炎症反应。在此，我们发现不同的钙离子内流通道决定了IFNγ诱导的M1或IL-4诱导的M2转变。幼稚或M2巨噬细胞表现出强烈的钙离子内流，这依赖于Orai1通道，而M1表型则显示出非选择性的TRPC1电流。钙离子内流的阻断抑制了pNF-κB/pJNK/STAT1或STAT6信号事件，从而降低了对M1或M2功能至关重要的细胞因子产生。重要的是，LPS刺激使M2细胞从Orai1介导的钙离子内流转为TRPC1介导的钙离子内流，并且TRPC1基因敲除小鼠表现出抑制促炎细胞因子的转录变化。相反，Orai1基因敲除巨噬细胞的抗炎细胞因子减少，线粒体氧消耗率受到抑制，并且特异性地抑制了M2细胞中的线粒体形态转变。最后，TRPC1或Orai1表达的改变决定了巨噬细胞极化，表明钙离子通道在调节巨噬细胞转变中具有独特作用。
