Resolving macrophage polarization through distinct Ca2+ entry channel that maintains intracellular signaling and mitochondrial bioenergetics
| Autor: | Paul F. Worley, Arun Chauhan, Karthik Ramachandran, Yuyang Sun, Bibhuti B. Mishra, Manigandan Venkatesan, Soumya Maity, Neelanjan Vishnu, Donald L. Gill, Brij B. Singh, Bony DeKumar, Amritha Raveendran, George A. Kotsakis, Muniswamy Madesh, Viviane Conceicao |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | iScience, Vol 24, Iss 11, Pp 103339-(2021) iScience |
| ISSN: | 2589-0042 |
| Popis: | Summary Transformation 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 abstract Highlights • 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 polarization Immune system; Molecular biology; Molecular network |
| Databáze: | OpenAIRE |
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