Canonical wnt signaling in dendritic cells regulates Th1/Th17 responses and suppresses autoimmune neuroinflammation.
Canonical wnt signaling in dendritic cells regulates Th1/Th17 responses and suppresses autoimmune neuroinflammation.
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DOI：
10.4049/jimmunol.1402691
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发表时间：
2015-04-01
期刊：
影响因子：
--
通讯作者：
Manicassamy S
中科院分区：
文献类型：
--
作者：
Suryawanshi A;Manoharan I;Hong Y;Swafford D;Majumdar T;Taketo MM;Manicassamy B;Koni PA;Thangaraju M;Sun Z;Mellor AL;Munn DH;Manicassamy S
对自身抗原的免疫耐受性的破坏或不受控制的炎症导致自身免疫性疾病。树突状细胞（Dendritic cells，DC）在调节外周炎症反应和调节反应之间的平衡中起重要作用。然而，组织微环境中的因素和对DC编程以控制慢性炎症和促进耐受性至关重要的信号网络尚不清楚。在这里，我们表明，wnt配体介导的β-catenin信号转导在DC中的激活对于促进耐受和限制神经炎症是至关重要的。小鼠中典型wnt信号传导的关键上游（LRP 5/6）或下游介质（β-连环蛋白）的DC特异性缺失加剧了实验性自身免疫性脑脊髓炎（EAE）病理学。从机制上讲，DC中LRP 5/6-β-连环蛋白介导的信号转导的缺失导致Th 1/Th 17细胞分化增加，而调节性T细胞应答降低。这是由于缺乏LRP 5/6-β-连环蛋白信号传导的DC的促炎细胞因子的产生增加和抗炎细胞因子如IL-10和IL-27的产生减少。与这些发现一致，经典wnt/β-连环蛋白信号传导的药理学激活延迟了EAE发作并减少了CNS病理学。因此，DC中经典wnt信号传导的激活限制了效应T细胞应答，并代表了控制自身免疫性神经炎症的潜在治疗方法。
Breakdown in immunological tolerance to self-antigens or uncontrolled inflammation results in autoimmune disorders. Dendritic cells (DCs) play an important role in regulating the balance between inflammatory and regulatory responses in the periphery. However, factors in the tissue microenvironment and the signaling networks critical for programming DCs to control chronic inflammation and promote tolerance are unknown. Here, we show that wnt ligand-mediated activation of β-catenin signaling in DCs is critical for promoting tolerance and limiting neuroinflammation. DC-specific deletion of key upstream (LRP5/6) or downstream mediators (β-catenin) of canonical wnt-signaling in mice exacerbated experimental autoimmune encephalomyelitis (EAE) pathology. Mechanistically, loss of LRP5/6-β-catenin-mediated signaling in DCs led to an increased Th1/ Th17 cell differentiation whereas reduced regulatory T cell response. This was due to increased production of pro-inflammatory cytokines and decreased production of anti-inflammatory cytokines such as IL-10 and IL-27 by DCs lacking LRP5/6-β-catenin signaling. Consistent with these findings, pharmacological activation of canonical wnt/β-catenin signaling delayed EAE onset and diminished CNS pathology. Thus, the activation of canonical wnt signaling in DCs limits effector T cell responses and represents a potential therapeutic approach to control autoimmune neuroinflammation.
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影响因子：
7.8
作者：
Manicassamy S;Pulendran B
通讯作者：
Pulendran B
DOI：
10.1038/nri3477
发表时间：
2013-08
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1084/jem.20062648
发表时间：
2007-07-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caton ML;Smith-Raska MR;Reizis B
通讯作者：
Reizis B
影响因子：
5.5
作者：
Liang, Xinjun;Fu, Chunmei;Jiang, Aimin
通讯作者：
Jiang, Aimin
影响因子：
8.7
作者：
Manicassamy S;Pulendran B
通讯作者：
Pulendran B