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Toll-like receptor 9 activation is a key mechanism for the maintenance of chronic lung inflammation.

American journal of respiratory and critical care medicine (2009-10-03)
Toshihiro Ito, Matthew Schaller, Tracy Raymond, Amrita D Joshi, Ana L Coelho, Fabiani G Frantz, William F Carson, Cory M Hogaboam, Nicholas W Lukacs, Theodore J Standiford, Sem H Phan, Stephen W Chensue, Steven L Kunkel
ABSTRACT

Accumulating evidence supports the hypothesis that the continuous host response to a persistent challenge can polarize the cytokine environment toward a Th2 cytokine phenotype, but the mechanisms responsible for this skewing are not clear. We investigated the role of Toll-like receptor 9 (TLR9) in a Th2-driven pulmonary granulomatous response initiated via the embolization of Schistosoma mansoni eggs to the lungs of mice. Mice were intravenously injected with S. mansoni eggs. Histological and flow cytometric analysis, cytokine measurement, adoptive transfer of bone marrow (BM)-derived dendritic cells (DCs), and in vitro T-cell treatments with antigen-presenting cells were examined. In comparison to wild-type mice, TLR9(-/-) mice showed increased pulmonary granuloma size, augmented collagen deposition, increased Th2 cytokine phenotype, and impaired accumulation of DCs. BM-derived DCs, but not macrophages, recovered from animals with developed Th2-type lung granulomas promoted the production of type 2 cytokines from CD4(+) T cells. BM-derived DCs from TLR9(-/-) mice induced impaired Th1 cytokine and enhanced Th2 cytokine production by T cells, compared with DCs from WT mice. Macrophages from TLR9(-/-) mice expressed a significantly higher alternatively activated (M2) phenotype characterized by increased "found in inflammatory zone-1" (FIZZ1) and arginase-1 expression. The adoptive transfer of BM-derived DCs from syngeneic WT mice into TLR9(-/-) mice restored the granuloma phenotype seen in WT mice. These studies suggest that TLR9 plays an important mechanistic role in the maintenance of the pulmonary granulomatous response.

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