Local inhibition of TGF-β1 signaling improves Th17/Treg balance but not joint pathology during experimental arthritis.
Local inhibition of TGF-β1 signaling improves Th17/Treg balance but not joint pathology during experimental arthritis.
复制标题
局部抑制TGF-β1信号传导可改善实验性关节炎中Th 17/Treg平衡，但不能改善关节病理学。
DOI：
10.1038/s41598-022-07075-w
复制
发表时间：
2022-02-24
影响因子：
4.6
通讯作者：
Koenders MI
中科院分区：
文献类型：
--
作者：
Aarts J;van Caam A;Chen X;Marijnissen RJ;Helsen MM;Walgreen B;Vitters EL;van de Loo FA;van Lent PL;van der Kraan PM;Koenders MI
TGF-β1是促进T辅助细胞17（Th 17）和调节性T细胞（Treg）分化的重要生长因子。TGF-β1作为T细胞介导的疾病如类风湿性关节炎（RA）的治疗靶点的潜力尚不清楚。我们研究了TGF-β1抑制对体外小鼠Th 17分化、体外人RA滑膜外植体和体内实验性关节炎发展的影响。将小鼠脾细胞诱导分化为Th 17细胞，观察TGF-βRI抑制剂SB-505124的作用。在存在或不存在SB-505124的情况下培养滑膜活检。在C57 B16小鼠中诱导实验性关节炎，并每天用SB-505124处理。进行流式细胞术分析以测量不同的T细胞亚群。分析组织切片以确定关节炎症和破坏。SB-505124通过降低Il 17 a和Rorc基因表达和IL-17蛋白产生，有效降低小鼠Th 17分化。SB-505124显著抑制滑膜外植体产生IL-6。在体内，SB-505124减少了Th 17的数量，而观察到Tcl 3的数量增加。尽管这种偏斜的Th 17/Treg平衡，SB-505124治疗没有导致关节炎症和破坏的抑制。阻断TGF-β1信号传导抑制Th 17分化并改善Th 17/Treg平衡。然而，局部SB-505124治疗不能抑制实验性关节炎。
TGF-β1 is an important growth factor to promote the differentiation of T helper 17 (Th17) and regulatory T cells (Treg). The potential of TGF-β1 as therapeutic target in T cell-mediated diseases like rheumatoid arthritis (RA) is unclear. We investigated the effect of TGF-β1 inhibition on murine Th17 differentiation in vitro, on human RA synovial explants ex vivo, and on the development of experimental arthritis in vivo. Murine splenocytes were differentiated into Th17 cells, and the effect of the TGF-βRI inhibitor SB-505124 was studied. Synovial biopsies were cultured in the presence or absence of SB-505124. Experimental arthritis was induced in C57Bl6 mice and treated daily with SB-505124. Flow cytometry analysis was performed to measure different T cell subsets. Histological sections were analysed to determine joint inflammation and destruction. SB-505124 potently reduced murine Th17 differentiation by decreasing Il17a and Rorc gene expression and IL-17 protein production. SB-505124 significantly suppressed IL-6 production by synovial explants. In vivo, SB-505124 reduced Th17 numbers, while increased numbers of Tregs were observed. Despite this skewed Th17/Treg balance, SB-505124 treatment did not result in suppression of joint inflammation and destruction. Blocking TGF-β1 signalling suppresses Th17 differentiation and improves the Th17/Treg balance. However, local SB-505124 treatment does not suppress experimental arthritis.
登录
查看更多内容
影响因子：
3.7
作者：
Broeren MG;de Vries M;Bennink MB;van Lent PL;van der Kraan PM;Koenders MI;Thurlings RM;van de Loo FA
通讯作者：
van de Loo FA
影响因子：
32.4
作者：
Marie, Julien C.;Liggitt, Denny;Rudensky, Alexander Y.
通讯作者：
Rudensky, Alexander Y.
影响因子：
15.3
作者：
FAVA, RA;OLSEN, NJ;TOWNES, AS
通讯作者：
TOWNES, AS
影响因子：
32.4
作者：
Li, Ming O.;Wan, Yisong Y.;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
影响因子：
15.9
作者：
Letterio, JJ;Geiser, AG;Roberts, AB
通讯作者：
Roberts, AB