Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20.
Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20.
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DOI：
10.1084/jem.20071108
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发表时间：
2008-02-18
期刊：
影响因子：
--
通讯作者：
Ma A
中科院分区：
文献类型：
--
作者：
Turer EE;Tavares RM;Mortier E;Hitotsumatsu O;Advincula R;Lee B;Shifrin N;Malynn BA;Ma A
宿主细胞上的Toll样受体（TLR）在稳态条件期间被微生物配体长期接合。这些信号不会引起未受干扰的小鼠的炎症免疫反应，即使它们在对抗微生物感染时驱动先天性和适应性免疫反应。A20是一种限制外源性TLR诱导信号的泛素修饰酶。我们发现，MyD 88依赖性TLR信号驱动自发T细胞和骨髓细胞活化，恶病质，并在A20缺陷小鼠中观察到过早死亡。我们已经使用广谱抗生素来证明这些组成型TLR信号是由肠道植物群驱动的。A20通过限制E3连接酶肿瘤坏死因子受体相关因子6的泛素化来限制TLR信号。这些结果揭示了严重的促炎性病理生理学，可以从稳态TLR信号以及A20在体内限制这些信号的关键作用。此外，A20通过抑制含有Toll/白细胞介素1受体结构域的衔接子诱导干扰素（IFN）β依赖性核因子κB信号而非IFN应答因子3信号来限制MyD 88非依赖性TLR信号。这些发现提供了新的见解如何调节生理TLR信号。
Toll-like receptors (TLRs) on host cells are chronically engaged by microbial ligands during homeostatic conditions. These signals do not cause inflammatory immune responses in unperturbed mice, even though they drive innate and adaptive immune responses when combating microbial infections. A20 is a ubiquitin-modifying enzyme that restricts exogenous TLR-induced signals. We show that MyD88-dependent TLR signals drive the spontaneous T cell and myeloid cell activation, cachexia, and premature lethality seen in A20-deficient mice. We have used broad spectrum antibiotics to demonstrate that these constitutive TLR signals are driven by commensal intestinal flora. A20 restricts TLR signals by restricting ubiquitylation of the E3 ligase tumor necrosis factor receptor–associated factor 6. These results reveal both the severe proinflammatory pathophysiology that can arise from homeostatic TLR signals as well as the critical role of A20 in restricting these signals in vivo. In addition, A20 restricts MyD88-independent TLR signals by inhibiting Toll/interleukin 1 receptor domain–containing adaptor inducing interferon (IFN) β–dependent nuclear factor κB signals but not IFN response factor 3 signaling. These findings provide novel insights into how physiological TLR signals are regulated.
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影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
影响因子：
56.9
作者：
Lee, EG;Boone, DL;Ma, A
通讯作者：
Ma, A
影响因子：
64.5
作者：
Marine, JC;Topham, DJ;Ihle, JN
通讯作者：
Ihle, JN
影响因子：
30.5
作者：
Boone, DL;Turer, EE;Ma, A
通讯作者：
Ma, A
DOI：
10.1073/pnas.93.20.11008
发表时间：
1996-10-01
影响因子：
11.1
作者：
Hirsch, E;Irikura, VM;Hirsh, D
通讯作者：
Hirsh, D