@article{cb55c620564b41319a1e91f7f46cb8b4,
title = "Resolving macrophage polarization through distinct Ca2+ entry channel that maintains intracellular signaling and mitochondrial bioenergetics",
abstract = "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.",
keywords = "Immune system, Molecular biology, Molecular network",
author = "{Nascimento Da Conceicao}, Viviane and Yuyang Sun and Karthik Ramachandran and Arun Chauhan and Amritha Raveendran and Manigandan Venkatesan and Bony DeKumar and Soumya Maity and Neelanjan Vishnu and Kotsakis, {George A.} and Worley, {Paul F.} and Gill, {Donald L.} and Mishra, {Bibhuti B.} and Muniswamy Madesh and Singh, {Brij B.}",
note = "Funding Information: This work was funded by grant support from the National Institutes of Health (R01DE017102; R01DE022765) awarded to B.B.S. This research was funded by the National Institutes of Health (R01GM109882, R01HL086699, R01HL142673, R01GM135760, and 1S10RR027327) to M.M. This work was partly supported by DOD/DHP-CDMRP PR181598P-1 and San Antonio Partnership for Precision Therapeutics (SAPPT) to M.M. The funders had no further role in study design, data analysis, and/or interpretation of the data. Flow Cytometry Facility is supported by UTHSCSA, NIH-NCI P30 CA054174-20, and UL1 TR001120. Conceptualization, methodology, and analysis, V.N.D.C. B.B.M. M.M. and B.B.S. Animal genotyping, experiments, data analysis, and interpretation, K.R. M.V. S.M. N.V. and M.M. Experimental investigation, V.N.D.C. Y.S. K.R. A.C. A.R. M.V. B.D. S.M. G.A.K. M.M. and B.B.M. Writing–review and editing, V.N.D.C. N.V. B.B.M. D.L.G. M.M. and B.B.S. The authors declare no competing interests. Funding Information: This work was funded by grant support from the National Institutes of Health ( R01DE017102 ; R01DE022765 ) awarded to B.B.S. This research was funded by the National Institutes of Health ( R01GM109882 , R01HL086699 , R01HL142673 , R01GM135760 , and 1S10RR027327 ) to M.M. This work was partly supported by DOD / DHP-CDMRP PR181598P-1 and San Antonio Partnership for Precision Therapeutics (SAPPT) to M.M. The funders had no further role in study design, data analysis, and/or interpretation of the data. Flow Cytometry Facility is supported by UTHSCSA , NIH-NCI P30 CA054174-20 , and UL1 TR001120 . Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = nov,
day = "19",
doi = "10.1016/j.isci.2021.103339",
language = "English (US)",
volume = "24",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "11",
}