Loss of Ca2+ entry via Orai-TRPC1 induces ER stress, initiating immune activation in macrophages

Viviane Nascimento Da Conceicao, Yuyang Sun, Emily K. Zboril, Jorge J. De la Chapa, Brij B. Singh

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Activation of cellular stresses is associated with inflammation; however, the mechanisms are not well identified. Here, we provide evidence that loss of Ca2+ 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 storedependent Ca2+ entry in macrophages prior to the activation of the unfolded protein response. The endogenous Ca2+ 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 Ca2+ 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 Ca2+ entry that prevents ER stress and inhibits cytokine production, and thus induced cell survival. These results suggest an unequivocal role of Ca2+ entry in modulating ER stress and in the induction of inflammation.

Original languageEnglish (US)
Article numberjcs237610
JournalJournal of cell science
Issue number5
StatePublished - Mar 2020


  • Ca modulation
  • ER stress
  • Immune activation
  • SOCE channels
  • TRPC1

ASJC Scopus subject areas

  • Cell Biology


Dive into the research topics of 'Loss of Ca2+ entry via Orai-TRPC1 induces ER stress, initiating immune activation in macrophages'. Together they form a unique fingerprint.

Cite this