Sepsis is a systemic inflammatory response syndrome with high mortality. It has been reported that brefeldin A-inhibited guanine nucleotide-exchange factor 1 (BIG1) is involved in the pathogenesis of sepsis. However, the mechanism is not fully elucidated. In the present study, we explored the role of BIG1 in mediating lipid raft-dependent macrophage inflammatory response and its impact on lung injury in murine sepsis. In vitro studies revealed that BIG1 deficiency reduces the upregulation and secretion of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-1β and inhibits the activation of the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88-dependent nuclear factor kappa-B signaling pathway induced by the lipopolysaccharide (LPS) treatment. Further experiments revealed that the inhibitory effects of BIG1 deficiency on LPS-induced inflammation are due to the upregulation of adenosine triphosphate-binding cassette transporter A1. This promotes the free-cholesterol efflux from lipid rafts and results in the reduction of lipid raft TLR4 content. The decrease in TLR4 content in lipid raft thereby inhibits the LPS-induced inflammatory response. Furthermore, using the cecal ligation and puncture-induced polymicrobial sepsis mouse model, we found that conditional knockout (cKO) of the myeloid cell BIG1 significantly reduced the serum concentrations of TNF-α, IL-6, and IL-1β, and downregulated their mRNA expressions in the lungs. Pathological analysis confirmed that the BIG1 cKO alleviated the sepsis-induced lung injury. These results revealed the crucial new role of BIG1 in mediating lipid raft-dependent macrophage inflammatory response. Hence, BIG1 may be a potential promising therapeutic target for the treatment of septic lung injury.

中文翻译：

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BIG1通过调节脂筏依赖性巨噬细胞炎症反应介导脓毒症诱导的肺损伤

脓毒症是一种死亡率很高的全身炎症反应综合征。据报道，brefeldin A 抑制的鸟嘌呤核苷酸交换因子 1 (BIG1) 参与败血症的发病机制。然而，该机制尚未完全阐明。在本研究中，我们探讨了 BIG1 在介导脂筏依赖性巨噬细胞炎症反应中的作用及其对鼠脓毒症肺损伤的影响。体外研究表明，BIG1 缺乏会降低肿瘤坏死因子 α (TNF-α)、白细胞介素-6 (IL-6) 和 IL-1β 的上调和分泌，并抑制 Toll 样受体 4 (TLR4)/髓细胞的激活脂多糖 (LPS) 处理诱导的分化初级反应 88 依赖性核因子 kappa-B 信号通路。进一步的实验表明，BIG1 缺乏对 LPS 诱导的炎症的抑制作用是由于三磷酸腺苷结合盒转运蛋白 A1 的上调。这促进了脂筏中游离胆固醇的流出并导致脂筏 TLR4 含量的减少。脂筏中TLR4含量的降低从而抑制了LPS诱导的炎症反应。此外，使用盲肠结扎和穿刺诱导的多微生物败血症小鼠模型，我们发现骨髓细胞 BIG1 的条件性敲除 (cKO) 显着降低了 TNF-α、IL-6 和 IL-1β 的血清浓度，并下调了它们在肺中的 mRNA 表达。病理分析证实 BIG1 cKO 减轻了败血症引起的肺损伤。这些结果揭示了 BIG1 在介导脂筏依赖性巨噬细胞炎症反应中的关键新作用。因此，BIG1 可能是治疗脓毒性肺损伤的潜在有希望的治疗靶点。这些结果揭示了 BIG1 在介导脂筏依赖性巨噬细胞炎症反应中的关键新作用。因此，BIG1 可能是治疗脓毒性肺损伤的潜在有希望的治疗靶点。这些结果揭示了 BIG1 在介导脂筏依赖性巨噬细胞炎症反应中的关键新作用。因此，BIG1 可能是治疗脓毒性肺损伤的潜在有希望的治疗靶点。