Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Am J Respir Crit Care Med. 2009 Dec 15;180(12):1227-38. doi: 10.1164/rccm.200906-0892OC. Epub 2009 Sep 24.
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.
越来越多的证据支持这样一种假说，即宿主对持续存在的挑战的持续反应可能使细胞因子环境向 Th2 细胞因子表型极化，但导致这种倾斜的机制尚不清楚。
我们研究了 Toll 样受体 9（TLR9）在通过栓塞曼氏血吸虫卵到小鼠肺部引发 Th2 驱动的肺部肉芽肿反应中的作用。
小鼠经静脉注射曼氏血吸虫卵。进行组织学和流式细胞术分析、细胞因子测量、骨髓（BM）来源树突状细胞（DC）的过继转移以及抗原呈递细胞体外 T 细胞处理。
与野生型小鼠相比，TLR9（-/-）小鼠的肺部肉芽肿增大，胶原沉积增加，Th2 细胞因子表型增强，DC 积累受损。从发生 Th2 型肺肉芽肿的动物中恢复的 BM 来源 DC，而不是巨噬细胞，促进了 CD4（+）T 细胞产生 2 型细胞因子。与 WT 小鼠的 DC 相比，来自 TLR9（-/-）小鼠的 BM 来源 DC 诱导 Th1 细胞因子产生受损，并增强 Th2 细胞因子的产生。来自 TLR9（-/-）小鼠的巨噬细胞表达了一种明显的高替代性激活（M2）表型，其特征是“炎症区 1 中发现的物质”（FIZZ1）和精氨酸酶-1 的表达增加。将来自同基因 WT 小鼠的 BM 来源 DC 的过继转移到 TLR9（-/-）小鼠中，恢复了 WT 小鼠中观察到的肉芽肿表型。
这些研究表明 TLR9 在维持肺部肉芽肿反应中发挥重要的机制作用。
