Th17 down-regulation is involved in reduced progression of schistosomiasis fibrosis in ICOSL KO mice.
Th17 down-regulation is involved in reduced progression of schistosomiasis fibrosis in ICOSL KO mice.
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DOI：
10.1371/journal.pntd.0003434
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发表时间：
2015-01
影响因子：
3.8
通讯作者：
Xia CM
中科院分区：
文献类型：
--
作者：
Wang B;Liang S;Wang Y;Zhu XQ;Gong W;Zhang HQ;Li Y;Xia CM
肉芽肿性和纤维化炎症反应的寄生虫卵是主要的病理发生在感染血吸虫属。CD 4 + T细胞在宿主抗寄生虫感染的免疫应答和血吸虫病的免疫病理学中起着关键作用，并协调许多类型的免疫细胞，这些免疫细胞有助于纤维化。ICOSL在控制T细胞活化、分化和功能的特定方面发挥重要作用。先前的工作表明ICOS对于Th 17细胞发育至关重要。然而，该通路在血吸虫病纤维化中的免疫发病机制尚不清楚。利用ICOSL KO和C57 BL/6 WT小鼠的血吸虫病模型，我们研究了ICOSL/ICOS相互作用在宿主肉芽肿性炎症中介导Th 17应答的作用，特别是在S.日本血吸虫感染，并研究在这些模型中的ICOSL KO小鼠的免疫应答和病理学。结果显示，ICOSL KO小鼠的存活率提高，寄生虫卵周围的肝肉芽肿性炎症减少，肝纤维化发展明显抑制，Th 17相关细胞因子水平降低，（IL-17/IL-21），Th 2相关细胞因子（IL-4/IL-6/IL-10）、促纤维化细胞因子（IL-13）和TGF-β1，但与野生型（WT）小鼠相比，Th 1相关细胞因子（IFN-γ）水平更高。纤维化进展的减少与Th 17和Th 2的下调以及ICOSL/ICOS相互作用的消除相关。我们的研究结果表明，IL-17产生细胞有助于肝肉芽肿性炎症和随后的纤维化。重要的是，在ICOSL KO小鼠中，IL-17产生细胞的存在与ICOS表达之间存在明显的正相关性，并且额外的结果表明，Th 17参与了血吸虫病诱导的肝纤维化的病理组织重塑。T细胞的完全活化和分化为Th 1、Th 2或Th 17细胞需要共刺激分子和细胞因子。ICOS也与慢性炎症有关，对Th 17细胞发育至关重要。在一些肝纤维化模型中，CD 4 + IL-17分泌性T细胞已被证明有助于病理学。然而，在血吸虫病纤维化中，该通路的意义和免疫发病机制均未阐明。本研究使用ICOSL KO小鼠来评估ICOSL/ICOS相互作用在介导宿主肉芽肿性炎症中的Th 17应答中的作用，特别是在日本血吸虫感染期间的肝纤维化中。本研究进一步阐明了血吸虫病肝纤维化的免疫调节机制，为血吸虫病肝纤维化的免疫发病机制研究提供了新的思路。这可能揭示新的治疗靶点，干扰肉芽肿中的Th 17细胞迁移或分化以及随后的S.山茱萸
Granulomatous and fibrosing inflammation in response to parasite eggs is the main pathology that occurs during infection with Schistosoma spp. CD4+ T cells play critical roles in both host immune responses against parasitic infection and immunopathology in schistosomiasis,and coordinate many types of immune cells that contribute to fibrosis. ICOSL plays an important role in controlling specific aspects of T cell activation, differentiation, and function. Previous work has suggested that ICOS is essential for Th17 cell development. However, the immunopathogenesis of this pathway in schistosomiasis fibrosisis still unclear. Using models of schistosomiasis in ICOSL KO and the C57BL/6 WT mice, we studied the role of the ICOSL/ICOS interaction in the mediation of the Th17 response in host granulomatous inflammation, particularly in liver fibrosis during S. japonicum infection, and investigated the immune responses and pathology of ICOSL KO mice in these models. The results showed that ICOSL KO mice exhibited improved survival, reduced liver granulomatous inflammation around parasite eggs, markedly inhibited hepatic fibrosis development, lower levels of Th17-related cytokines (IL-17/IL-21), Th2-related cytokines (IL-4/IL-6/IL-10), a pro-fibrotic cytokine (IL-13), and TGF-β1, but higher level of Th1-related cytokine (IFN-γ) compared to wild-type (WT) mice. The reduced progression of fibrogenesis was correlated with the down-regulation of Th17 and Th2 and the elimination of ICOSL/ICOS interactions. Our findings suggest that IL-17-producing cells contribute to the hepatic granulomatous inflammation and subsequent fibrosis. Importantly, there was a clearly positive correlation between the presence of IL-17-producing cells and ICOS expression in ICOSL KO mice, and additional results indicated that Th17 was involved in the pathological tissue remodeling in liver fibrosis induced by schistosomiasis. The full activation and differentiation of T cells into Th1, Th2 or Th17 cells requires costimulatory molecules and cytokines. ICOS has also been implicated in chronic inflammation and is critical for Th17 cell development. CD4+ IL-17-secreting T cells have been shown to contribute to pathology in some models of liver fibrosis. However, neither the significance nor the immunopathogenesis of this pathway have been elucidated in schistosomiasis fibrosis. The present study used the ICOSL KO mice to assess the role of the ICOSL/ICOS interaction in the mediation of the Th17 response in host granulomatous inflammation, particularly in liver fibrosis during S.japonicum infection. This study further clarifies the immune regulatory mechanism of fibrosis and sheds light on the understanding of the immunopathogenesis of Schistosoma-induced fibrosis. It might reveal new therapeutic targets that interfere with Th17 cell migration or differentiation in granulomas and the subsequent fibrosis following infection with S. japonicum.
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DOI：
10.1084/jem.194.6.809
发表时间：
2001-09-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lee CG;Homer RJ;Zhu Z;Lanone S;Wang X;Koteliansky V;Shipley JM;Gotwals P;Noble P;Chen Q;Senior RM;Elias JA
通讯作者：
Elias JA
DOI：
10.1084/jem.192.1.53
发表时间：
2000-07-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kopf M;Coyle AJ;Schmitz N;Barner M;Oxenius A;Gallimore A;Gutierrez-Ramos JC;Bachmann MF
通讯作者：
Bachmann MF
影响因子：
64.8
作者：
Dong, C;Juedes, AE;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
4.3
作者：
Chen, Bo-Lin;Zhang, Gui-Ying;Li, Jia
通讯作者：
Li, Jia
影响因子：
3.7
作者：
Clay, Bryan S.;Shilling, Rebecca A.;Sperling, Anne I.
通讯作者：
Sperling, Anne I.