TLR2-dependent activation of β-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation.
TLR2-dependent activation of β-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation.
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DOI：
10.4049/jimmunol.1400614
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发表时间：
2014-10-15
期刊：
影响因子：
--
通讯作者：
Manicassamy S
中科院分区：
文献类型：
--
作者：
Manoharan I;Hong Y;Suryawanshi A;Angus-Hill ML;Sun Z;Mellor AL;Munn DH;Manicassamy S
树突状细胞（DC）通过多种先天受体感知微生物。来自不同先天受体的信号由DC协调和整合以产生针对病原体的特异性先天性和适应性免疫应答。以前，我们已经表明，两个病原体识别受体，TLR 2和dectin-1，识别相同的微生物刺激（酵母聚糖）对树突状细胞，诱导相互拮抗的调节或炎症反应，分别。来自这两种受体的直接信号如何在DC中协调以调节或激发免疫尚不清楚。在这里，我们表明，TLR 2信号通过AKT激活β-catenin/TCF 4通路在DC和程序，他们驱动调节性T细胞分化。β-catenin/TCF 4的激活对于诱导调节分子白细胞介素-10（IL-10）和维生素A代谢酶视黄醇脱氢酶2（Aldh 1a 2）以及抑制促炎细胞因子是至关重要的。DCs中β-catenin的缺失使它们响应酵母聚糖而驱动TH 17/TH 1细胞分化。与这些发现一致，DC中β-连环蛋白通路的激活抑制慢性炎症并保护小鼠免受TH 17/TH 1介导的自身免疫性神经炎症。因此，通过TLR 2受体激活DC中的β-连环蛋白是DC中调节自身免疫性炎症的新机制。
Dendritic cells (DCs) sense microbes via multiple innate receptors. Signals from different innate receptors are coordinated and integrated by DCs to generate specific innate and adaptive immune responses against pathogens. Previously, we have shown that two pathogen recognition receptors, TLR2 and dectin-1 that recognize the same microbial stimulus (zymosan) on DCs, induce mutually antagonistic regulatory or inflammatory responses, respectively. How diametric signals from these two receptors are coordinated in DCs to regulate or incite immunity is not known. Here we show that TLR2-signaling via AKT activates the β-catenin/TCF4 pathway in DCs and programs them to drive T regulatory cell differentiation. Activation of β-catenin/TCF4 was critical to induce regulatory molecules interleukin-10 (Il-10) and vitamin A metabolizing enzyme retinaldehyde dehydrogenase 2 (Aldh1a2) and to suppress pro-inflammatory cytokines. Deletion of β-catenin in DCs programmed them to drive TH17/TH1 cell differentiation in response to zymosan. Consistent with these findings, activation of the β-catenin pathway in DCs suppressed chronic inflammation and protected mice from TH17/TH1-mediated autoimmune neuroinflammation. Thus activation of β-catenin in DCs via the TLR2 receptor is a novel mechanism in DCs that regulates autoimmune inflammation.
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DOI：
10.1084/jem.20021890
发表时间：
2003-05-05
期刊：
The Journal of experimental medicine
影响因子：
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