KLF6 contributes to myeloid cell plasticity in the pathogenesis of intestinal inflammation.
KLF6 contributes to myeloid cell plasticity in the pathogenesis of intestinal inflammation.
复制标题
KLF6 在肠道炎症的发病机制中有助于骨髓细胞的可塑性。
DOI：
10.1038/mi.2016.1
复制
发表时间：
2016-09
影响因子：
8
通讯作者：
Mahabeleshwar GH
中科院分区：
文献类型：
--
作者：
Goodman WA;Omenetti S;Date D;Di Martino L;De Salvo C;Kim GD;Chowdhry S;Bamias G;Cominelli F;Pizarro TT;Mahabeleshwar GH
炎症性肠病（IBD）与巨噬细胞应答失调相关，使得静止巨噬细胞获得促炎活化状态并促成慢性肠道炎症。在慢性炎症如IBD的背景下，控制巨噬细胞活化和基因表达的转录事件仍不完全清楚。在这里，我们确定Kruppel样转录因子-6（KLF 6）作为人类和实验性IBD中致病性骨髓细胞活化的关键调节因子。我们发现，KLF 6在IBD患者和IBD实验模型的骨髓细胞和肠组织中显著上调，特别是在结肠的活动性炎症区域。利用功能获得和功能丧失的互补研究，我们观察到KLF 6通过增强NFκB信号促进促炎基因表达，同时通过抑制STAT 3信号抑制抗炎基因表达。为了研究髓样KLF 6的体内作用，我们用葡聚糖硫酸钠（DSS）处理髓样特异性KLF 6敲除小鼠（Mac-KLF 6-KO），发现Mac-KLF 6-KO小鼠可免受化学诱导的结肠炎的影响;这突出了髓样KLF 6在促进肠道炎症中的核心作用。总的来说，我们的研究结果指出了一个新的基因调控程序的基础致病性，促炎性巨噬细胞激活的慢性肠道炎症的设置。
Inflammatory bowel disease (IBD) is associated with dysregulated macrophage responses, such that quiescent macrophages acquire a pro-inflammatory activation state and contribute to chronic intestinal inflammation. The transcriptional events governing macrophage activation and gene expression in the context of chronic inflammation such as IBD remain incompletely understood. Here, we identify Kruppel-like transcription factor-6 (KLF6) as a critical regulator of pathogenic myeloid cell activation in human and experimental IBD. We found that KLF6 was significantly upregulated in myeloid cells and intestinal tissue from IBD patients and experimental models of IBD, particularly in actively inflamed regions of the colon. Using complementary gain- and loss-of-function studies, we observed that KLF6 promotes pro-inflammatory gene expression through enhancement of NFκB signaling, while simultaneously suppressing anti-inflammatory gene expression through repression of STAT3 signaling. To study the in vivo role of myeloid KLF6, we treated myeloid-specific KLF6-knockout mice (Mac-KLF6-KO) with dextran sulfate-sodium (DSS) and found that Mac-KLF6-KO mice were protected against chemically-induced colitis; this highlights the central role of myeloid KLF6 in promoting intestinal inflammation. Collectively, our results point to a novel gene regulatory program underlying pathogenic, pro-inflammatory macrophage activation in the setting of chronic intestinal inflammation.