BIG1 mediates sepsis-induced lung injury by modulating lipid raft-dependent macrophage inflammatory responses
BIG1 mediates sepsis-induced lung injury by modulating lipid raft-dependent macrophage inflammatory responses
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DOI：
10.1093/abbs/gmab085
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发表时间：
2021-06-21
影响因子：
3.7
通讯作者：
Fang, Hao
中科院分区：
文献类型：
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作者：
Sun, Minli;Han, Xiaodan;Fang, Hao
脓毒症是一种全身性炎症反应综合征，病死率高。已有研究表明，灯盏花素A抑制的鸟苷核苷酸交换因子1(BIG1)参与了脓毒症的发病过程。然而，其作用机制尚未完全阐明。在本研究中，我们探讨了BIG1在介导脂筏依赖的巨噬细胞炎症反应中的作用及其对脓毒症小鼠肺损伤的影响。体外研究表明，BIG1缺乏可降低肿瘤坏死因子α(TNF-α)、白介素6(IL-6)和白介素1β(IL-1β)的表达和分泌，并抑制脂多糖(LPS)诱导的Toll样受体4(TLR4)/髓系分化初级反应88依赖的核因子-kappa-B信号通路的激活。进一步的实验表明，BIG1缺乏对内毒素诱导的炎症的抑制作用是由于三磷酸腺苷结合盒转运体A1上调所致。这促进了游离胆固醇从脂筏流出，并导致脂筏TLR4含量的减少。脂筏中TLR4含量减少，从而抑制内毒素诱导的炎症反应。此外，在盲肠结扎和穿刺法诱导的多菌败血症小鼠模型中，我们发现髓系细胞BIG1的条件敲除(CKO)显著降低了血清中TNF-α、IL-6和IL-1β的浓度，并下调了它们在肺组织中的mRNA表达。病理分析证实，BIG1 CKO可减轻脓毒症所致的肺损伤。这些结果揭示了BIG1在介导脂筏依赖的巨噬细胞炎症反应中的关键新作用。因此，BIG1可能成为治疗感染性肺损伤的潜在靶点。
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-alpha), interleukin-6 (IL-6), and IL-1 beta 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-alpha, IL-6, and IL-1 beta, 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.