TLR3-activated monocyte-derived dendritic cells trigger progression from acute viral infection to chronic disease in the lung

Xinyu Wang, Kangyun Wu, Shamus P. Keeler, Dailing Mao, Eugene V. Agapov, Yong Zhang, Michael J. Holtzman

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Acute infection is implicated as a trigger for chronic inflammatory disease, but the full basis for this switch is uncertain. 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 monocytederived dendritic cells (moDCs) was selectively required to induce long-term expression of IL-33 and consequent type 2 immunedriven 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.

Original languageEnglish
Pages (from-to)1297-1314
Number of pages18
JournalJournal of Immunology
Volume206
Issue number6
DOIs
StatePublished - Mar 15 2021

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