Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models
Abstract Ca2+ entry via Ca2+ release-activated Ca2+ (CRAC) channels is a predominant mechanism of intracellular Ca2+ 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 i...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41065-4 |
| _version_ | 1797558588157198336 |
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| author | Emily Howard Benjamin P. Hurrell Doumet Georges Helou Pedram Shafiei-Jahani Spyridon Hasiakos Jacob Painter Sonal Srikanth Yousang Gwack Omid Akbari |
| author_facet | Emily Howard Benjamin P. Hurrell Doumet Georges Helou Pedram Shafiei-Jahani Spyridon Hasiakos Jacob Painter Sonal Srikanth Yousang Gwack Omid Akbari |
| author_sort | Emily Howard |
| collection | DOAJ |
| description | Abstract Ca2+ entry via Ca2+ release-activated Ca2+ (CRAC) channels is a predominant mechanism of intracellular Ca2+ 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 Ca2+ signaling in ILC2 biology, providing potential insights into the development of therapies for the treatment of allergic and atopic inflammatory diseases. |
| first_indexed | 2024-03-10T17:32:37Z |
| format | Article |
| id | doaj.art-6ea722380e2340a785089d7d327b7642 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:32:37Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-6ea722380e2340a785089d7d327b76422023-11-20T09:57:20ZengNature PortfolioNature Communications2041-17232023-09-0114111310.1038/s41467-023-41065-4Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized modelsEmily Howard0Benjamin P. Hurrell1Doumet Georges Helou2Pedram Shafiei-Jahani3Spyridon Hasiakos4Jacob Painter5Sonal Srikanth6Yousang Gwack7Omid Akbari8Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern CaliforniaDepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern CaliforniaDepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern CaliforniaDepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern CaliforniaDepartment of Physiology, David Geffen School of Medicine, University of CaliforniaDepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern CaliforniaDepartment of Physiology, David Geffen School of Medicine, University of CaliforniaDepartment of Physiology, David Geffen School of Medicine, University of CaliforniaDepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern CaliforniaAbstract Ca2+ entry via Ca2+ release-activated Ca2+ (CRAC) channels is a predominant mechanism of intracellular Ca2+ 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 Ca2+ signaling in ILC2 biology, providing potential insights into the development of therapies for the treatment of allergic and atopic inflammatory diseases.https://doi.org/10.1038/s41467-023-41065-4 |
| spellingShingle | Emily Howard Benjamin P. Hurrell Doumet Georges Helou Pedram Shafiei-Jahani Spyridon Hasiakos Jacob Painter Sonal Srikanth Yousang Gwack Omid Akbari Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models Nature Communications |
| title | Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models |
| title_full | Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models |
| title_fullStr | Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models |
| title_full_unstemmed | Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models |
| title_short | Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models |
| title_sort | orai inhibition modulates pulmonary ilc2 metabolism and alleviates airway hyperreactivity in murine and humanized models |
| url | https://doi.org/10.1038/s41467-023-41065-4 |
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