Myeloid cell TBK1 restricts inflammatory responses.
Myeloid cell TBK1 restricts inflammatory responses.
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DOI：
10.1073/pnas.2107742119
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发表时间：
2022-01-25
影响因子：
11.1
通讯作者：
Sun SC
中科院分区：
文献类型：
--
作者：
Gao T;Liu T;Ko CJ;Zhang L;Joo D;Xie X;Zhu L;Li Y;Cheng X;Sun SC
巨噬细胞在慢性炎症性疾病如非酒精性脂肪性肝炎（NASH）和炎症性肠病中起着至关重要的作用，但巨噬细胞的促炎功能如何控制尚不清楚。在这项工作中，我们将TBK 1确定为巨噬细胞中的关键抗炎因子，可限制不同疾病模型中的炎症。骨髓细胞特异性TBK 1缺乏导致老年小鼠自发发生代谢紊乱，并加重高脂饮食诱导的脂肪肝疾病伴NASH样症状。Tbk 1-MKO小鼠也对实验性结肠炎过敏。我们获得的遗传证据表明，TBK 1是控制巨噬细胞中促炎信号通路的关键。这些发现确立了TBK 1作为一种关键的抗炎因子和治疗炎症性疾病的潜在治疗靶点。先天免疫细胞产生的促炎细胞因子在炎症性疾病中起着至关重要的作用，但控制炎症反应的分子机制知之甚少。在这里，我们表明TANK结合激酶1（TBK 1）作为促炎巨噬细胞功能的重要调节因子，并保护组织免受炎症。髓样细胞条件性Tbk 1敲除（MKO）小鼠在老年时自发发生脂肪肥大和代谢紊乱，与脂肪组织M1巨噬细胞浸润和促炎细胞因子表达增加相关。当喂食高脂肪饮食时，Tbk 1-MKO小鼠也表现出肝脏炎症和胰岛素抵抗加剧，出现非酒精性脂肪性肝炎的症状。此外，骨髓细胞特异性TBK 1消融加剧了实验性结肠炎的炎症。从机制上讲，TBK 1在巨噬细胞中发挥作用，抑制NF-κB和MAP激酶信号通路，从而减弱促炎细胞因子（特别是IL-1β）的诱导。IL-1受体1（IL-1 R1）的消融消除了Tbk 1-MKO小鼠的炎症症状。这些结果确立了TBK 1作为一种关键的抗炎介质，在不同的疾病模型中限制炎症。
Macrophages play a crucial role in chronic inflammatory diseases, such as nonalcoholic steatohepatitis (NASH) and inflammatory bowel disease, but how the proinflammatory function of macrophages is controlled is not well understood. In this work, we identified TBK1 as a pivotal anti-inflammatory factor in macrophages that restricts inflammation in different disease models. Myeloid cell–specific TBK1 deficiency causes spontaneous development of metabolic disorders in aged mice and exacerbates high-fat diet–induced fatty liver disease with NASH-like symptoms. The Tbk1-MKO mice are also hypersensitive to experimental colitis. We obtained genetic evidence that TBK1 is crucial for controlling proinflammatory signaling pathway in macrophages. These findings establish TBK1 as a pivotal anti-inflammatory factor and a potential therapeutic target for the treatment of inflammatory diseases. Proinflammatory cytokine production by innate immune cells plays a crucial role in inflammatory diseases, but the molecular mechanisms controlling the inflammatory responses are poorly understood. Here, we show that TANK-binding kinase 1 (TBK1) serves as a vital regulator of proinflammatory macrophage function and protects against tissue inflammation. Myeloid cell–conditional Tbk1 knockout (MKO) mice spontaneously developed adipose hypertrophy and metabolic disorders at old ages, associated with increased adipose tissue M1 macrophage infiltration and proinflammatory cytokine expression. When fed with a high-fat diet, the Tbk1-MKO mice also displayed exacerbated hepatic inflammation and insulin resistance, developing symptoms of nonalcoholic steatohepatitis. Furthermore, myeloid cell–specific TBK1 ablation exacerbates inflammation in experimental colitis. Mechanistically, TBK1 functions in macrophages to suppress the NF-κB and MAP kinase signaling pathways and thus attenuate induction of proinflammatory cytokines, particularly IL-1β. Ablation of IL-1 receptor 1 (IL-1R1) eliminates the inflammatory symptoms of Tbk1-MKO mice. These results establish TBK1 as a pivotal anti-inflammatory mediator that restricts inflammation in different disease models.
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