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Increasing evidence indicates that activated lung macrophages play a significant role in the initiation, intensity, progression, and resolution of allergic airway inflammation. However, the underlying mechanisms regulating macrophage-mediated inflammation in asthma remain incompletely understood. Our previous work revealed increased mitochondrial DNA (mtDNA) depletion and mitochondrial damages in the lungs of asthmatic mice, implicating mitochondrial dysfunction in disease pathogenesis. Given that mitochondrial transcription factor A (TFAM) is essential for mtDNA maintenance and integrity, we hypothesized that TFAM has a fundamental role in regulating mtDNA stress and downstream inflammtroy response in asthma. Using myeloid-specific TFAM knockout (TFAM\n                  <jats:sup>fl\/fl<\/jats:sup>\n                  LysMcre, TFAM KO) mice subjected to allergens sensitization and challenge, we observed pronounced mitochondrial dysfunction and accentuated asthmatic inflammation. This was accompanied by elevated expression of asthma-associated mediators, including il-13, muc5a\/c, muc5b, and ccl17. In addition, TFAM deficiency was associated with increased eosinophilia and and cytosolic mtDNA release, contributing to exacerbated airway pathology. Together, we have identified a critical role of TFAM in myeloid cells that contributes to asthmatic airway inflammation. These results suggest that therapeutic restoration of TFAM function may offer a novel strategy to mitigate mitochondrial stress, reduce airway inflammation, and improve outcomes in patients with moderate to severe asthma.\n                <\/jats:p>","DOI":"10.1101\/2025.05.27.654580","type":"posted-content","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T23:40:11Z","timestamp":1748389211000},"source":"Crossref","is-referenced-by-count":1,"title":["Myeloid-specific TFAM deficiency drives mitochondrial DNA stress and exacerbates allergic airway inflammation"],"prefix":"10.64898","author":[{"given":"Jackie","family":"Nguyen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Courtney","family":"Van","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manjula","family":"Karpurapu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiyoung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tae Jin","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji Young","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Navjot","family":"Pabla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John W.","family":"Christman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sangwoon","family":"Chung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025052908050741000_2025.05.27.654580v1.1","doi-asserted-by":"crossref","unstructured":"M.P. 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