Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage-myofibroblast transition
Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage-myofibroblast transition
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DOI：
10.1073/pnas.1917663117
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发表时间：
2020-08-25
影响因子：
11.1
通讯作者：
Lan, Hui-Yao
中科院分区：
文献类型：
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作者：
Tang, Patrick Ming-Kuen;Zhang, Ying-ying;Lan, Hui-Yao
未解决的炎症可导致组织纤维化和器官功能受损。巨噬细胞 - 肌成纤维细胞转化（MMT）是一种新发现的机制，通过该机制，持续的慢性炎症在不同形式的肾脏疾病中导致进行性纤维化。然而，MMT的潜在机制在很大程度上仍然未知。在此，我们发现一种脑特异性同源盒/POU结构域蛋白Pou4f1（Brn3a）是MMT的一种特异性调节因子。有趣的是，我们发现Pou4f1在人类和实验性肾脏疾病纤维化部位正在发生MMT的巨噬细胞中高度表达，这通过肌成纤维细胞标志物α - SMA的共表达得以确定。出乎意料的是，Pou4f1在体内肾纤维化的早期以及体外骨髓来源巨噬细胞（BMDMs）的MMT过程中表达达到峰值。从机制上讲，染色质免疫沉淀（ChIP）分析确定Pou4f1是Smad3的靶标以及MMT的关键下游调节因子，而微阵列分析在转录水平上确定了一个依赖于Pou4f1的促纤维化基因网络，用于促进BMDMs中TGF - β1/Smad3驱动的MMT。更重要的是，利用两种具有MMT过程的进行性肾间质纤维化小鼠模型，我们证明了TGF - β1刺激的BMDMs过继转移恢复了巨噬细胞耗竭小鼠的MMT和肾纤维化，而在转移的BMDMs中沉默Pou4f1可阻止这种情况。这些发现确立了Pou4f1在MMT和肾纤维化中的作用，并表明Pou4f1可能是伴有进行性肾纤维化的慢性肾脏病的一个治疗靶点。
Unresolved inflammation can lead to tissue fibrosis and impaired organ function. Macrophage-myofibroblast transition (MMT) is one newly identified mechanism by which ongoing chronic inflammation causes progressive fibrosis in different forms of kidney disease. However, the mechanisms underlying MMT are still largely unknown. Here, we discovered a brain-specific homeobox/POU domain protein Pou4f1 (Brn3a) as a specific regulator of MMT. Interestingly, we found that Pou4f1 is highly expressed by macrophages undergoing MMT in sites of fibrosis in human and experimental kidney disease, identified by coexpression of the myofibroblast marker, alpha-SMA. Unexpectedly, Pou4f1 expression peaked in the early stage in renal fibrogenesis in vivo and during MMT of bone marrow-derived macrophages (BMDMs) in vitro. Mechanistically, chromatin immunoprecipitation (ChIP) assay identified that Pou4f1 is a Smad3 target and the key downstream regulator of MMT, while microarray analysis defined a Pou4f1-dependent fibrogenic gene network for promoting TGF-beta 1/Smad3-driven MMT in BMDMs at the transcriptional level. More importantly, using two mouse models of progressive renal interstitial fibrosis featuring the MMT process, we demonstrated that adoptive transfer of TGF-beta 1-stimulated BMDMs restored both MMT and renal fibrosis in macrophage-depleted mice, which was prevented by silencing Pou4f1 in transferred BMDMs. These findings establish a role for Pou4f1 in MMT and renal fibrosis and suggest that Pou4f1 may be a therapeutic target for chronic kidney disease with progressive renal fibrosis.