Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models
Year: 2023
Type: article
Abstract: Ca 2+ entry via Ca 2+ release-activated Ca 2+ (CRAC) channels is a predominant mechanism of intracellular Ca 2+ 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. Mechanistically, ILC2 metabolic and mitochondrial homeostasis are inhibited and lead to the upregulation of reactive oxygen species production. We confirm our findings in human ILC2s, as blocking Orai1 and Orai2 prevents the development of airway hyperreactivity in humanized mice. Our findings have a broad impact on the basic understanding of Ca 2+ signaling in ILC2 biology, providing potential insights into the development of therapies for the treatment of allergic and atopic inflammatory diseases.
Source: Nature Communications
Language: English
Topic: IL-33, ST2, and ILC Pathways
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
Awards: G1189123816, Induction of cells and pathways that promote respiratory tolerance in allergic asthma, Regulation of the STING pathway under sterile conditions, Maternal effect on offspring immunity against hepatitis B virus, G2116375177, G3345712455, G4705405167, G4919436967, G4950121257, Mechanism underlying regulation of Ca2+ signaling in local effector T cells, G6391327092, Distinctive role of ORAI3 channels in the effector T cell response, Gene expression in myeloma cells, G8456926422, Study the link of autophagy dysfunction to allergic and neutrophilic asthma onset, UCLA Dental Specialty PhD Program, Transcriptional and metabolomic regulation of IL-10 in pulmonary ILC2s, Role of TNF receptor 2 on Pulmonary Group 2 Innate Lymphoid Cells
OpenAlex ID: W4387050820