Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models.

Ca entry via Ca release-activated Ca (CRAC) channels is a predominant mechanism of intracellular Ca elevation in immune cells. Here we show the immunoregulatory role of CRAC channel components Orai1 and Orai2 in Group 2 innate lymphoid cells (ILC2s), that play crucial roles in the induction of type 2 inflammation. We find that blocking or genetic ablation of Orai1 and Orai2 downregulates ILC2 effector function and cytokine production, consequently ameliorating the development of ILC2-mediated airway inflammation in multiple murine models.

ORAI1 Limits SARS-CoV-2 Infection by Regulating Tonic Type I IFN Signaling.

ORAI1 and stromal interaction molecule 1 (STIM1) are the critical mediators of store-operated Ca entry by acting as the pore subunit and an endoplasmic reticulum-resident signaling molecule, respectively. In addition to Ca signaling, STIM1 is also involved in regulation of the type I IFN (IFN-I) response. To examine their potential role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we generated and knockout human HEK293-angiotensin-converting enzyme 2 cells and checked their responses.