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

Author

Listed:
  • Emily Howard

    (University of Southern California)

  • Benjamin P. Hurrell

    (University of Southern California)

  • Doumet Georges Helou

    (University of Southern California)

  • Pedram Shafiei-Jahani

    (University of Southern California)

  • Spyridon Hasiakos

    (University of California)

  • Jacob Painter

    (University of Southern California)

  • Sonal Srikanth

    (University of California)

  • Yousang Gwack

    (University of California)

  • Omid Akbari

    (University of Southern California)

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.

Suggested Citation

  • Emily Howard & Benjamin P. Hurrell & Doumet Georges Helou & Pedram Shafiei-Jahani & Spyridon Hasiakos & Jacob Painter & Sonal Srikanth & Yousang Gwack & Omid Akbari, 2023. "Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41065-4
    DOI: 10.1038/s41467-023-41065-4
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    References listed on IDEAS

    as
    1. Martin Vaeth & Jun Yang & Megumi Yamashita & Isabelle Zee & Miriam Eckstein & Camille Knosp & Ulrike Kaufmann & Peter Karoly Jani & Rodrigo S. Lacruz & Veit Flockerzi & Imre Kacskovics & Murali Prakri, 2017. "ORAI2 modulates store-operated calcium entry and T cell-mediated immunity," Nature Communications, Nature, vol. 8(1), pages 1-17, April.
    2. Lauriane Galle-Treger & Yuzo Suzuki & Nisheel Patel & Ishwarya Sankaranarayanan & Jennifer L. Aron & Hadi Maazi & Lin Chen & Omid Akbari, 2016. "Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    3. Doumet Georges Helou & Pedram Shafiei-Jahani & Richard Lo & Emily Howard & Benjamin P. Hurrell & Lauriane Galle-Treger & Jacob D. Painter & Gavin Lewis & Pejman Soroosh & Arlene H. Sharpe & Omid Akbar, 2020. "PD-1 pathway regulates ILC2 metabolism and PD-1 agonist treatment ameliorates airway hyperreactivity," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
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