Loss of Ca 2+ entry via Orai-TRPC1 induces ER stress, initiating immune activation in macrophages.
| Autor: | Nascimento Da Conceicao V; Department of Periodontics, School of Dentistry, University of Texas Health San Antonio, San Antonio, TX 78229, USA., Sun Y; Department of Periodontics, School of Dentistry, University of Texas Health San Antonio, San Antonio, TX 78229, USA., Zboril EK; Department of Periodontics, School of Dentistry, University of Texas Health San Antonio, San Antonio, TX 78229, USA., De la Chapa JJ; Department of Comprehensive Dentistry, School of Dentistry, University of Texas Health San Antonio, San Antonio, TX 78229, USA., Singh BB; Department of Periodontics, School of Dentistry, University of Texas Health San Antonio, San Antonio, TX 78229, USA singhbb@uthscsa.edu. |
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| Jazyk: | angličtina |
| Zdroj: | Journal of cell science [J Cell Sci] 2019 Dec 18; Vol. 133 (5). Date of Electronic Publication: 2019 Dec 18. |
| DOI: | 10.1242/jcs.237610 |
| Abstrakt: | Activation of cellular stresses is associated with inflammation; however, the mechanisms are not well identified. Here, we provide evidence that loss of Ca 2+ influx induces endoplasmic reticulum (ER) stress in primary macrophages and in murine macrophage cell line Raw 264.7, in which the unfolded protein response is initiated to modulate cytokine production, thereby activating the immune response. Stressors that initiate the ER stress response block store-dependent Ca 2+ entry in macrophages prior to the activation of the unfolded protein response. The endogenous Ca 2+ entry channel is dependent on the Orai1-TRPC1-STIM1 complex, and the presence of ER stressors decreased expression of TRPC1, Orai1 and STIM1. Additionally, blocking Ca 2+ entry with SKF96365 also induced ER stress, promoted cytokine production, activation of autophagy, increased caspase activation and induced apoptosis. Furthermore, ER stress inducers inhibited cell cycle progression, promoted the inflammatory M1 phenotype, and increased phagocytosis. Mechanistically, restoration of Orai1-STIM1 expression inhibited the ER stress-mediated loss of Ca 2+ entry that prevents ER stress and inhibits cytokine production, and thus induced cell survival. These results suggest an unequivocal role of Ca 2+ entry in modulating ER stress and in the induction of inflammation. Competing Interests: Competing interestsThe authors declare no competing or financial interests. (© 2019. Published by The Company of Biologists Ltd.) |
| Databáze: | MEDLINE |
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