{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T02:03:19Z","timestamp":1789524199283,"version":"build-2803163510"},"reference-count":120,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"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>\n                    Asthma exacerbations are predominantly triggered by respiratory viral infections, yet current therapies largely fail to restore effective antiviral immunity. Emerging data indicate that this failure is tightly coupled to dysregulated immunometabolism within the asthmatic lung. This review advances the concept of a dendritic cell\u2013natural killer (DC\u2013NK) metabolic checkpoint, whereby the metabolic state of DCs, regulated by autophagy and AMPK\/mTOR signaling, licenses NK cells for antiviral effector function. In type 2-high, type 2\u2212low, and obesity-related asthma endotypes, chronic hypoxia, HIF\u22121\u03b1 stabilization, ORMDL3\u2013ceramide signaling, and systemic metabolic stress converge to induce highly glycolytic, Th2\/Th17\u2212polarizing DCs in a lactate-rich, acidic microenvironment. We propose that these DCs modulate NK cell metabolism through three interlinked axes: (i) cytokine-mediated metabolic licensing (IL\u221212, IL\u221215, IL\u221218), (ii) exosome-mediated delivery of activating versus metabolically suppressive cargo, and (iii) intense perisynaptic nutrient competition that depletes local glucose while lactate accumulation and acidosis further inhibit NK cell function. The result is a \u201cdouble metabolic hit\u201d that renders lung-resident NK cells metabolically exhausted, IFN\u2212\u03b3\u2212deficient, and unable to clear virally infected targets despite preserved cytotoxic machinery. Although many mechanistic insights derive from murine and\n                    <jats:italic>in vitro<\/jats:italic>\n                    models, converging human metabolomic, genetic, and functional data support this framework and define clear research gaps. If validated in human studies, targeting the DC-NK cell metabolic checkpoint with agents that restore autophagic plasticity, rebalance AMPK\/mTOR signaling, or normalize airway nutrient and pH landscapes may represent a promising strategy to prevent viral-triggered asthma exacerbations.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1798209","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T04:21:17Z","timestamp":1775103677000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Metabolic licensing at the dendritic cell\u2013NK cells immune synapse in viral asthma exacerbations"],"prefix":"10.3389","volume":"17","author":[{"given":"Yan-Jiao","family":"Chen","sequence":"first","affiliation":[{"name":"Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1016\/s2213-2600(17)30293-x","article-title":"Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: A systematic analysis for the global burden of disease study 2015","volume":"5","year":"2017","journal-title":"Lancet Respir Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.310.6989.1225","article-title":"Community study of role of viral infections in exacerbations of asthma in 9\u201311 year old children","volume":"310","author":"Johnston","year":"1995","journal-title":"Bmj"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041901","article-title":"Asthmatic bronchial epithelial cells have a deficient innate immune 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