{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T03:43:25Z","timestamp":1789875805697,"version":"4.0.1"},"reference-count":79,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Allergic asthma is characterized by type 2 inflammation and overnight worsening of symptoms, yet dynamic fluxes in cellular metabolic profiles driving time-of-day variation remain poorly defined. Group 2 innate lymphoid cells (ILC2s) are central mediators of airway hyperreactivity. We identify melatonin as a previously unrecognized regulator of ILC2 metabolism and function. In murine models of allergic airway inflammation, melatonin reduced eosinophilia, type 2 cytokine production, and airway hyperreactivity without altering ILC2 abundance. Mechanistically, melatonin acted independently of canonical melatonin receptors and instead reprogrammed ILC2 metabolism toward pentose phosphate pathway activity, enhancing NADPH generation and NRF2-dependent glutathione accumulation. Metabolic profiling, loss-of-function approaches, and pharmacologic activation studies demonstrated that NRF2 is both necessary and sufficient to restrain ILC2 effector function. Importantly, primary human ILC2s exhibited conserved NRF2 activation, glutathione accumulation, and reduced type 2 cytokine production in response to melatonin, underscoring clinical relevance. Together, these findings identify the melatonin-NRF2-glutathione axis as a metabolic checkpoint regulating innate type 2 immunity and suggest that therapeutic targeting of redox metabolism may represent a strategy for modulating airway inflammation in allergic asthma.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1845654","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T04:26:49Z","timestamp":1778473609000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Melatonin suppresses ILC2-driven airway hyperreactivity via glutathione-dependent metabolic reprogramming"],"prefix":"10.3389","volume":"17","author":[{"given":"Jafar","family":"Cain","sequence":"first","affiliation":[{"name":"Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin P.","family":"Hurrell","sequence":"additional","affiliation":[{"name":"Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Speliakos","sequence":"additional","affiliation":[{"name":"Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omid","family":"Akbari","sequence":"additional","affiliation":[{"name":"Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12916-016-0657-8","article-title":"The epidemiology, healthcare and societal burden and costs of asthma in the UK and its member nations: analyses of standalone and linked national databases","volume":"14","author":"Mukherjee","year":"2016","journal-title":"BMC Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-2600(20)30105-3","article-title":"Prevalence and attributable health burden of chronic respiratory diseases, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017","volume":"8","year":"2020","journal-title":"Lancet Respir Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1056\/nejm199201303260504","article-title":"Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma","volume":"326","author":"Robinson","year":"1992","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.g5517","article-title":"Asthma: pathogenesis and novel drugs for treatment","volume":"349","author":"Olin","year":"2014","journal-title":"BMJ"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nature08636","article-title":"Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells","volume":"463","author":"Moro","year":"2010","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1111\/all.70030","article-title":"The expanding role of ILC2s in allergic airways disease","volume":"81","author":"Cain","year":"2026","journal-title":"Allergy"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s00408-006-0017-0","article-title":"Comparison of 4 AM and 4 PM bronchial responsiveness to hypertonic saline in asthma","volume":"184","author":"Ferraz","year":"2006","journal-title":"Lung"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2005.09.028","article-title":"Nocturnal asthma","volume":"116","author":"Sutherland","year":"2005","journal-title":"J Allergy Clin Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1042\/cs20220061","article-title":"Circadian regulation of pulmonary disease: the importance of timing","volume":"137","author":"Cunningham","year":"2023","journal-title":"Clin Sci (Lond)"},{"key":"B10","article-title":"Caelii Aureliani \u2026 De morbis acutis & chronicis libri 8. soli ex omnium methodicorum scriptis superstites. 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