Microbiota regulates type 1 diabetes through Toll-like receptors
Microbiota regulates type 1 diabetes through Toll-like receptors
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DOI：
10.1073/pnas.1508740112
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发表时间：
2015-08-11
影响因子：
11.1
通讯作者：
Chervonsky, Alexander V.
中科院分区：
文献类型：
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作者：
Burrows, Michael P.;Volchkov, Pavel;Chervonsky, Alexander V.
在1型糖尿病（T1 D）的非肥胖糖尿病（NOD）小鼠模型中，先天免疫适应性髓样分化初级反应基因88（MyD 88）的缺失导致微生物群依赖性疾病保护：MyD 88阴性小鼠在无菌（GF）条件下，但在无特定病原体条件下不会发生疾病。这些结果可以通过特定保护性细菌的扩增（“特定谱系假说”）或通过突变小鼠中负（耐受性）信号传导对促炎信号传导的优势（“平衡信号假说”）来解释。在这里，我们发现GF小鼠与各种肠道细菌的定植能够减少MyD 88阴性（但不是野生型NOD小鼠）的T1 D，有利于平衡信号假说。然而，参与预防或促进疾病的受体和信号通路仍然未知。通过测试缺乏MyD 88的NOD小鼠，结合敲除先天免疫传感的几个关键组分以发展T1 D，揭示了微生物群触发的保护信号。只有MyD 88-和TIR-结构域含有衔接子诱导IFN β（TRIF）双缺陷NOD小鼠发展的疾病。因此，TRIF信号传导（可能在Toll样受体4，TLR 4的下游）充当微生物群诱导的耐受化途径之一。与此同时，另一种TLR（TLR 2）通过控制微生物群提供促糖尿病信号传导，因为由TLR 2缺失引起的T1 D发病率的降低在GF TLR 2阴性小鼠中被逆转。我们的研究结果支持平衡信号假说，即微生物通过不同的受体（包括TLR家族的受体）提供促进和抑制自身免疫的信号。
Deletion of the innate immune adaptor myeloid differentiation primary response gene 88 (MyD88) in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D) results in microbiota-dependent protection from the disease: MyD88-negative mice in germfree (GF), but not in specific pathogen-free conditions develop the disease. These results could be explained by expansion of particular protective bacteria ("specific lineage hypothesis") or by dominance of negative (tolerizing) signaling over proinflammatory signaling ("balanced signal hypothesis") in mutant mice. Here we found that colonization of GF mice with a variety of intestinal bacteria was capable of reducing T1D in MyD88-negative (but not wild-type NOD mice), favoring the balanced signal hypothesis. However, the receptors and signaling pathways involved in prevention or facilitation of the disease remained unknown. The protective signals triggered by the microbiota were revealed by testing NOD mice lacking MyD88 in combination with knockouts of several critical components of innate immune sensing for development of T1D. Only MyD88-and TIR-domain containing adapter inducing IFN beta (TRIF) double deficient NOD mice developed the disease. Thus, TRIF signaling (likely downstream of Toll-like receptor 4, TLR4) serves as one of the microbiota-induced tolerizing pathways. At the same time another TLR (TLR2) provided prodiabetic signaling by controlling the microbiota, as reduction in T1D incidence caused by TLR2 deletion was reversed in GF TLR2-negative mice. Our results support the balanced signal hypothesis, in which microbes provide signals that both promote and inhibit autoimmunity by signaling through different receptors, including receptors of the TLR family.