摘要：SummaryTransformation of naive macrophages into classically (M1) or alternatively (M2) activated macrophages regulates the inflammatory response. Here, we identified that distinct Ca2+entry channels determine the IFNγ-induced M1 or IL-4-induced M2 transition. Naive or M2 macrophages exhibit a robust Ca2+entry that was dependent on Orai1 channels, whereas the M1 phenotype showed a non-selective TRPC1 current. Blockade of Ca2+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 Ca2+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 Ca2+channels in modulating macrophage transformation.Graphical abstractDisplay OmittedHighlights•Store-operated Ca2+entry is essential for macrophage activation and function•Orai1 activation of STAT6 dictates the anti-inflammatory M2 phenotype•TRPC1-mediated activation of pNF-κB/STAT1 is critical for M1 phenotype•Alteration in TRPC1/Orai1 expression transforms M1/M2 polarizationImmune system; Molecular biology; Molecular network
