Department of Pharmacology & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
Department of Anesthesiology, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai, China.
Cell Death Dis. 2020 May 15;11(5):374. doi: 10.1038/s41419-020-2590-1.
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-α, IL-6, IL-1β, 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.
脓毒症是由严重感染引起的宿主炎症反应失调导致危及生命的器官功能障碍引起的。其高发病率和死亡率使得脓毒症仍然是一个主要的临床问题。在这里，我们研究了 Brefeldin A 抑制的鸟嘌呤核苷酸交换因子 1（BIG1）在脓毒症发病机制中的作用及其潜在机制。我们发现髓样细胞特异性 BIG1 敲除（BIG1 cKO）显著降低了 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 小鼠的血清浓度和促炎细胞因子（包括 TNF-α、IL-6、IL-1β 和 IL-12）的 mRNA 表达明显降低。在骨髓来源的巨噬细胞或 THP-1 细胞中，BIG1 缺乏导致 ARF3 激活受到抑制，这通过抑制 LPS 诱导的 PIP5K 激活来减少 PI(4,5)P2 的合成和 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 作为脓毒症的潜在有希望的治疗靶点提供了证据。
