期刊
JOURNAL OF IMMUNOLOGY
卷 206, 期 6, 页码 1297-1314出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.2000965
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资金
- National Institute of Allergy and Infectious Diseases [R01 AI130591]
- National Heart, Lung, and Blood Institute [R35 HL145242]
- Cystic Fibrosis Foundation [P19-06099]
- Hardy Trust
- Schaeffer Funds
The study found that following respiratory infection, monocyte-derived dendritic cells participate in the development of chronic lung disease through a non-canonical TLR3 signaling pathway, expanding the population of alveolar epithelial type 2 cells to provide a persistent immune response.
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.
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