Tim-4 Inhibits NLRP3 Inflammasome via the LKB1/AMPKα Pathway in Macrophages
Tim-4 Inhibits NLRP3 Inflammasome via the LKB1/AMPKα Pathway in Macrophages
复制标题
Tim-4 通过巨噬细胞中的 LKB1/AMPK α 通路抑制 NLRP3 炎症小体
DOI：
10.4049/jimmunol.1900117
复制
发表时间：
2019-08-15
影响因子：
4.4
通讯作者：
Gao, Lifen
中科院分区：
文献类型：
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作者：
Liu, Wen;Bai, Fuxiang;Gao, Lifen
非酒精性脂肪性肝病（NAFLD）是最常见的代谢性肝病之一，以过度炎症和脂质沉积为特征。NAFLD时巨噬细胞内NLRP 3炎性小体表达明显增加，其激活使NAFLD加重。Tim-4作为磷脂酰丝氨酸（PS）受体在巨噬细胞中高度表达，并且巨噬细胞Tim-4在各种免疫激活条件下抑制炎症。然而，Tim-4在NLRP 3炎性小体调节和NAFLD发病机制中的确切作用仍然完全未知。采用NAFLD小鼠模型，通过Western blot、实时荧光定量PCR、免疫组化和免疫荧光等方法证实Tim-4在肝组织中的表达增加，尤其是在肝巨噬细胞中的表达更高，并且Tim-4敲除小鼠在NAFLD小鼠模型中表现出比对照更严重的肝脏炎症和肝脏脂肪变性。在体外实验中，我们发现Tim-4可以抑制NLRP 3炎性小体的活化，并且这种抑制作用依赖于IgV结构域中的PS结合结构域。从机制上讲，Tim-4通过激活AMPK α介导的自噬诱导NLRP 3炎性体组分的降解。具体地说，Tim-4通过与LKB 1和AMPK α相互作用促进AMPK α磷酸化。此外，PS结合基序负责Tim-4介导的AMPK α和LKB 1相互作用。总之，NAFLD微环境上调巨噬细胞中的Tim-4表达，并且升高的Tim-4反过来通过激活LKB 1/AMPK α介导的自噬来抑制NLRP 3炎性体激活，从而改善IL-1 β和IL-18的释放。总的来说，这项研究揭示了Tim-4在抑制NLRP 3炎性小体方面的新功能，这将为通过靶向Tim-4干预NAFLD或炎症性肝病提供新的思路。
Nonalcoholic fatty liver disease (NAFLD), characterized by excessive inflammation and lipid deposition, is one of the most common metabolic liver diseases. The expression of NLRP3 inflammasome in macrophages is significantly increased in NAFLD, and its activation aggravates NAFLD greatly. Tim-4, as the phosphatidylserine (PS) receptor, is expressed highly in macrophages, and macrophage Tim-4 inhibits inflammation under various conditions of immune activation. However, the precise role of Tim-4 in NLRP3 inflammasome regulation and NAFLD pathogenesis remains completely unknown. Using NAFLD mice models, we confirmed that the expression of Tim-4 was increased in liver tissues by Western blot, real-time PCR, immunohistochemistry, and immunofluorescence, especially higher expression in liver macrophages, and Tim-4 knockout mice displayed more severe liver inflammation and hepatic steatosis than controls in NAFLD mice model. In vitro, we found that Tim-4 could inhibit NLRP3 inflammasome activation, and the inhibition was dependent on PS binding domain in the IgV domain. Mechanistically, Tim-4 induced the degradation of NLRP3 inflammasome components through activating AMPK alpha-mediated autophagy. Specifically, Tim-4 promoted AMPK alpha phosphorylation by interacting with LKB1 and AMPK alpha. In addition, PS binding motif was responsible for Tim-4-mediated AMPK alpha and LKB1 interaction. In conclusion, NAFLD microenvironments upregulate Tim-4 expression in macrophages, and elevated Tim-4, in turn, suppresses NLRP3 inflammasome activation by activating LKB1/AMPK alpha-mediated autophagy, thereby ameliorating the release of IL-1 beta and IL-18. Collectively, this study unveils the novel function of Tim-4 in suppressing NLRP3 inflammasome, which would shed new lights on intervention of NAFLD or inflammatory liver diseases by targeting Tim-4.