Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality
Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality
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DOI：
10.1189/jlb.0210071
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发表时间：
2010-12-01
影响因子：
5.5
通讯作者：
Hall, J. Perry
中科院分区：
文献类型：
--
作者：
Marchlik, Erica;Thakker, Paresh;Hall, J. Perry
TBK1对于激活TLR4和TLR3依赖的信号通路的微生物病原体的免疫至关重要。为了阐明TBK1在炎症中的作用，研究人员培育了携带两个突变的TBK1等位基因拷贝的小鼠。这种TBK1(Delta)等位基因编码一种截短的TBK1(Delta)蛋白，该蛋白在催化作用下是不活跃的，并且在非常低的水平上表达。在内毒素刺激下，TBK1(Delta/Delta)小鼠的巨噬细胞产生正常水平的促炎细胞因子(如肿瘤坏死因子-α)，但干扰素-β和RANTES的表达以及IRF3 DNA结合活性被消融。三个月大的TBK1(Delta/Delta)小鼠在多个器官中表现出单核细胞和肉芽肿细胞的渗透，皮肤中有炎性细胞渗透，它们的循环单核细胞数量是它们的TBK1(+/-)和TBK1(+/Delta)小鼠的两倍。2周龄的TBK1(Delta/Delta)小鼠的皮肤以反应性变化为特征，包括角化过度、增生、坏死、炎性细胞浸润和水肿。作为对内毒素攻击的响应，3月龄的TBK1(Delta/Delta)小鼠的死亡速度和死亡人数都比它们的TBK1(+/+)和TBK1(+/Delta)小鼠更快和更多。这种致死性伴随着TBK1(Delta/Delta)小鼠血清中几种致炎细胞因子的过度产生，包括TNF-α、GM-CSF、IL-6和KC。TBK1(Delta/Delta)小鼠在内毒素攻击后血清细胞因子的过度产生和对内毒素致死性的增加可能是由于其较大的循环单核细胞隔室和较多的外渗免疫细胞的反应所致。J.Leukoc。比奥尔。88：1171-1180；2010。
TBK1 is critical for immunity against microbial pathogens that activate TLR4- and TLR3-dependent signaling pathways. To address the role of TBK1 in inflammation, mice were generated that harbor two copies of a mutant Tbk1 allele. This Tbk1(Delta) allele encodes a truncated Tbk1(Delta) protein that is catalytically inactive and expressed at very low levels. Upon LPS stimulation, macrophages from Tbk1(Delta/Delta) mice produce normal levels of proinflammatory cytokines (e.g., TNF-alpha), but IFN-beta and RANTES expression and IRF3 DNA-binding activity are ablated. Three-month-old Tbk1(Delta/Delta) mice exhibit mononuclear and granulomatous cell infiltrates in multiple organs and inflammatory cell infiltrates in their skin, and they harbor a 2-fold greater amount of circulating monocytes than their Tbk1(+/-) and Tbk1(+/Delta) littermates. Skin from 2-week-old Tbk1(Delta/Delta) mice is characterized by reactive changes, including hyperkeratosis, hyperplasia, necrosis, inflammatory cell infiltrates, and edema. In response to LPS challenge, 3-month-old Tbk1(Delta/Delta) mice die more quickly and in greater numbers than their Tbk1(+/+) and Tbk1(+/Delta) counterparts. This lethality is accompanied by an overproduction of several proinflammatory cytokines in the serum of Tbk1(Delta/Delta) mice, including TNF-alpha, GM-CSF, IL-6, and KC. This overproduction of serum cytokines in Tbk1(Delta/Delta) mice following LPS challenge and their increased susceptibility to LPS-induced lethality may result from the reactions of their larger circulating monocyte compartment and their greater numbers of extravasated immune cells. J. Leukoc. Biol. 88: 1171-1180; 2010.