BIG1 controls macrophage pro-inflammatory responses through ARF3-mediated PI(4,5)P2 synthesis
BIG1 controls macrophage pro-inflammatory responses through ARF3-mediated PI(4,5)P2 synthesis
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DOI：
10.1038/s41419-020-2590-1
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发表时间：
2020-05-15
影响因子：
9
通讯作者：
Shen, Xiaoyan
中科院分区：
文献类型：
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作者：
Liu, Lixin;Zhang, Sulin;Shen, Xiaoyan
脓毒症是由宿主对严重感染的炎症反应失调引起的，导致危及生命的器官功能障碍。高发病率和死亡率使脓毒症仍然是一个主要的临床问题。在此，我们研究了布雷菲德菌素A抑制鸟嘌呤核苷酸交换因子1（BIG1）在脓毒症发病过程中的作用及其潜在机制。我们发现骨髓细胞特异性 BIG1 敲除 (BIG1 cKO) 显着降低了 LPS 诱导和 CLP 诱导的多微生物脓毒症小鼠模型的死亡率和器官损伤。 BIG1 cKO小鼠中促炎细胞因子（包括TNF-α、IL-6、IL-1β和IL-12）的血清浓度和mRNA表达明显降低。在骨髓源性巨噬细胞或THP-1细胞中，BIG1缺陷导致ARF3激活受到抑制，从而通过抑制LPS诱导的PIP5K激活来减少PI(4,5)P2合成和TIRAP向质膜的募集，最终导致TLR4-MyD88信号通路的抑制活性。这些结果揭示了 BIG1 在调节巨噬细胞炎症反应中的重要新作用，并为 BIG1 作为败血症的潜在治疗靶点提供了证据。
Sepsis is caused by a dysregulated host inflammatory response to serious infections resulting in life-threatening organ dysfunction. The high morbidity and mortality make sepsis still a major clinical problem. Here, we investigated the roles of Brefeldin A-inhibited guanine nucleotide-exchange factor 1 (BIG1) in the pathogenesis process of sepsis and the underlying mechanisms. We found myeloid cell-specific BIG1 knockout (BIG1 cKO) significantly reduced the mortality and organ damage in LPS-induced and CLP-induced polymicrobial sepsis mouse model. The serum concentration and mRNA expression of pro-inflammatory cytokines including TNF-alpha, IL-6, IL-1 beta, and IL-12 were obviously decreased in BIG1 cKO mice. In bone marrow-derived macrophages or THP-1 cells, BIG1 deficiency caused an inhibited ARF3 activation, which reduced PI(4,5)P2 synthesis and the recruitment of TIRAP to the plasma membrane through inhibiting the activation of PIP5K induced by LPS, and eventually resulted in the inhibitory activity of TLR4-MyD88 signaling pathway. These results reveal a crucial new role of BIG1 in regulating macrophage inflammation responses, and provide evidence for BIG1 as a potential promising therapeutic target in sepsis.