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In this study, we examine this issue using a mouse model of chronic lung disease that develops after respiratory infection with a natural pathogen (Sendai virus). We investigate this model using a combination of TLR3-deficient mice and adoptive transfer of immune cells into these mice versus the comparable responses in wild-type mice. We found that acute and transient expression of TLR3 on monocyte-derived dendritic cells (moDCs) was selectively required to induce long-term expression of IL-33 and consequent type 2 immune-driven lung disease. Unexpectedly, moDC participation was not based on canonical TLR3 signaling and relied instead on a trophic effect to expand the alveolar epithelial type 2 cell population beyond repair of tissue injury and thereby provide an enriched and persistent cell source of IL-33 required for progression to a disease phenotype that includes lung inflammation, hyperreactivity, excess mucus production, and remodeling. The findings thereby provide a framework wherein viral infection activates TLR3 in moDCs as a front-line immune cell niche upstream of lung epithelial cells to drive the type 2 immune response, leading to chronic inflammatory diseases of the lung (such as asthma and chronic obstructive pulmonary disease in humans) and perhaps progressive and long-term postviral disease in general.<\/jats:p>","DOI":"10.4049\/jimmunol.2000965","type":"journal-article","created":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T18:30:23Z","timestamp":1611945023000},"page":"1297-1314","source":"Crossref","is-referenced-by-count":27,"title":["TLR3-Activated Monocyte-Derived Dendritic Cells Trigger Progression from Acute Viral Infection to Chronic Disease in the Lung"],"prefix":"10.1093","volume":"206","author":[{"given":"Xinyu","family":"Wang","sequence":"first","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine , St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8093-094X","authenticated-orcid":false,"given":"Kangyun","family":"Wu","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine , St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1301-0852","authenticated-orcid":false,"given":"Shamus P","family":"Keeler","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine , St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dailing","family":"Mao","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine , St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene V","family":"Agapov","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine , St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1620-2646","authenticated-orcid":false,"given":"Yong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine , St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8750-3716","authenticated-orcid":false,"given":"Michael J","family":"Holtzman","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine , St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,15]]},"reference":[{"key":"2025030502024048900_r1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1152\/physrev.00020.2001","article-title":"Immunity, inflammation, and remodeling in the airway epithelial barrier: epithelial-viral-allergic paradigm","volume":"82","author":"Holtzman","year":"2002","journal-title":"Physiol. 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