Unc93B1 Restricts Systemic Lethal Inflammation by Orchestrating Toll-like Receptor 7 and 9 Trafficking
Unc93B1 Restricts Systemic Lethal Inflammation by Orchestrating Toll-like Receptor 7 and 9 Trafficking
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DOI：
10.1016/j.immuni.2011.05.010
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发表时间：
2011-07-22
期刊：
影响因子：
32.4
通讯作者：
Miyake, Kensuke
中科院分区：
文献类型：
--
作者：
Fukui, Ryutaro;Saitoh, Shin-Ichiroh;Miyake, Kensuke
Toll样受体-7（TLR 7）和TLR 9是微生物RNA或DNA的先天免疫传感器，与自身免疫有关。激活后，TLR 7和9从内质网（ER）转运到内溶酶体，通过ER驻留蛋白Unc 93 B1进行核酸传感。然而，很少有人知道传感器运输在控制自身免疫中的作用。TLR 9与TLR 7竞争Unc 93 B1依赖性运输，并超过TLR 7。TLR 9偏斜由Unc 93 B1主动维持，并且如果Unc 93 B1通过D34 A突变失去优先结合，则逆转为TLR 7。我们在这里证明，携带D34 A突变的小鼠表现出TLR 7依赖性，全身性致死性炎症。CD 4（+）T细胞向辅助性T细胞1（Th 1）或Th 17细胞亚群分化明显。B细胞耗竭消除了T细胞分化和全身炎症。因此，Unc 93 B1通过平衡TLR 9至TLR 7运输来控制稳态TLR 7活化。
Toll-like receptor-7 (TLR7) and 9, innate immune sensors for microbial RNA or DNA, have been implicated in autoimmunity. Upon activation, TLR7 and 9 are transported from the endoplasmic reticulum (ER) to endolysosomes for nucleic acid sensing by an ER-resident protein, Unc93B1. Little is known, however, about a role for sensor transportation in controlling autoimmunity. TLR9 competes with TLR7 for Unc93B1-dependent trafficking and predominates over TLR7. TLR9 skewing is actively maintained by Unc93B1 and reversed to TLR7 if Unc93B1 loses preferential binding via a D34A mutation. We here demonstrate that mice harboring a D34A mutation showed TLR7-dependent, systemic lethal inflammation. CD4(+) T cells showed marked differentiation toward T helper 1 (Th1) or Th17 cell subsets. B cell depletion abolished T cell differentiation and systemic inflammation. Thus, Unc93B1 controls homeostatic TLR7 activation by balancing TLR9 to TLR7 trafficking.