4-1BB Signaling Promotes Alveolar Macrophages-Mediated Pro-Fibrotic Responses and Crystalline Silica-Induced Pulmonary Fibrosis in Mice.
4-1BB Signaling Promotes Alveolar Macrophages-Mediated Pro-Fibrotic Responses and Crystalline Silica-Induced Pulmonary Fibrosis in Mice.
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4-1BB 信号传导促进小鼠肺泡巨噬细胞介导的促纤维化反应和结晶二氧化硅诱导的肺纤维化。
DOI：
10.3389/fimmu.2018.01848
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发表时间：
2018
影响因子：
7.3
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Lu Y;Li C;Du S;Chen X;Zeng X;Liu F;Chen Y;Chen J
硅肺是由暴露于结晶二氧化硅（CS）引起的。我们以前已经表明，阻断4-1BB信号转导减弱CS诱导的炎症和肺纤维化。然而，表达4-1BB的细胞在促进纤维化中起着至关重要的作用，仍然是未知的。在这项研究中，我们证明了4-1BB的表达升高，在肺泡巨噬细胞（AM）在CS损伤的小鼠肺。CS暴露也显著增强巨噬细胞样MH-S细胞中4-1BB的表达。在这些细胞中，用激动剂抗体激活4-1BB信号传导导致促纤维化介质的分泌上调。一致地，阻断4-1BB下游信号传导或4-1BB的基因缺失减轻了体外促纤维化反应，而用4-1BB融合蛋白治疗促进了促纤维化反应。体内实验表明，阻断4-1BB信号转导可降低促纤维化介质的表达和纤维化。这些数据表明，4-1BB信号在促进AM介导的促纤维化反应和肺纤维化中起重要作用。我们的研究结果可能提供一个潜在的分子靶点，以减少CS诱导的职业性肺疾病的纤维化反应。
Silicosis is caused by exposure to crystalline silica (CS). We have previously shown that blocking 4-1BB signaling attenuated CS-induced inflammation and pulmonary fibrosis. However, the cells that express 4-1BB, which plays a vital role in promoting fibrosis, are still unknown. In this study, we demonstrated that the expression of 4-1BB is elevated in alveolar macrophages (AMs) in the lungs of CS-injured mice. CS exposure also markedly enhanced the expression of 4-1BB in macrophage-like, MH-S cells. In these cells, activation of the 4-1BB signaling with an agonist antibody led to upregulated secretion of pro-fibrotic mediators. Consistently, blocking 4-1BB downstream signaling or genetic deletion of 4-1BB alleviated pro-fibrotic responses in vitro, while treatment with a 4-1BB fusion protein promoted pro-fibrotic responses. In vivo experiments showed that blocking 4-1BB signaling decreased the expressions of pro-fibrotic mediators and fibrosis. These data suggest that 4-1BB signaling plays an important role in promoting AMs-mediated pro-fibrotic responses and pulmonary fibrosis. Our findings may provide a potential molecular target to reduce CS-induced fibrotic responses in occupational lung disease.
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