PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis
PTPN2 links colonic and joint inflammation in experimental autoimmune arthritis
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PTP2与实验性自身免疫性关节炎的结肠和关节炎症有关
DOI：
10.1172/jci.insight.141868
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发表时间：
2020-10-15
期刊：
影响因子：
8
通讯作者：
Bottini, Nunzio
中科院分区：
文献类型：
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作者：
Hsieh, Wan-Chen;Svensson, Mattias N. D.;Bottini, Nunzio
蛋白酪氨酸磷酸酶非受体2型（PTPN 2）的功能丧失变体增加了炎症性肠病和类风湿性关节炎的风险;然而，PTPN 2和自身免疫性关节炎之间的关联是否取决于肠道炎症尚不清楚。在这里，我们证明，诱导亚临床肠道炎症加剧发展的自身免疫性关节炎在SKG小鼠。Ptpn 2-单倍不足SKG小鼠-模拟PTPN 2疾病相关变体的人类携带者-显示出增强的结肠炎诱导的关节炎和表达RAR相关孤儿受体γ T（ROR-gamma t）的T细胞亚群的关节积聚-这是一种肠道富集的Treg亚群，可以转化为FoxP 3 IL-17（+）致关节炎性外突蛋白。SKG结肠TcR与外周TcR相比，转化为致关节炎性外TcR的程度更高，而Ptpn 2的单倍不足则加剧了这种转化。Ptpn 2单倍不足导致关节炎小鼠中表达结肠标记物G蛋白偶联受体15（GPR 15）的ROR γ t表达Tclase的选择性联合蓄积，并选择性增强GPR 15（+）的转化。在体外和体内将TdR转化为exTdR。Ptpn 2的可诱导Treg特异性单倍不足增强结肠炎诱导的SKG关节炎，并导致GPR 15（+）的特异性关节积聚。external.我们的数据验证了SKG模型在肠道和关节炎症之间的界面研究，并表明PTPN 2的致关节炎变体通过将结肠TdR转化为exTdR来放大肠道炎症和关节炎之间的联系。
Loss-of-function variants of protein tyrosine phosphatase non-receptor type 2 (PTPN2) enhance risk of inflammatory bowel disease and rheumatoid arthritis; however, whether the association between PTPN2 and autoimmune arthritis depends on gut inflammation is unknown. Here we demonstrate that induction of subclinical intestinal inflammation exacerbates development of autoimmune arthritis in SKG mice. Ptpn2-haploinsufficient SKG mice - modeling human carriers of disease-associated variants of PTPN2 - displayed enhanced colitis-induced arthritis and joint accumulation of Tregs expressing RAR-related orphan receptor gamma T (ROR-gamma t) - a gut-enriched Treg subset that can undergo conversion into FoxP3 IL-17(+) arthritogenic exTregs. SKG colonic Tregs underwent higher conversion into arthritogenic exTregs when compared with peripheral Tregs, which was exacerbated by haploinsufficiency of Ptpn2. Ptpn2 haploinsufficiency led to selective joint accumulation of ROR gamma t-expressing Tregs expressing the colonic marker G protein-coupled receptor 15 (GPR15) in arthritic mice and selectively enhanced conversion of GPR15(+). Tregs into exTregs in vitro and in vivo. Inducible Treg-specific haploinsufficiency of Ptpn2 enhanced colitis-induced SKG arthritis and led to specific joint accumulation of GPR15(+). exTregs. Our data validate the SKG model for studies at the interface between intestinal and joint inflammation and suggest that arthritogenic variants of PTPN2 amplify the link between gut inflammation and arthritis through conversion of colonic Tregs into exTregs.