Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation
Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation
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Fbxw7增加CX3CR1hi巨噬细胞中的CCL2/7促进肠道炎症
DOI：
10.1172/jci123374
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发表时间：
2019-09-03
影响因子：
15.9
通讯作者：
Wang, Qingqing
中科院分区：
文献类型：
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作者：
He, Jia;Song, Yinjing;Wang, Qingqing
肠道中具有功能可塑性的驻留和炎性单核吞噬细胞（MPhs）在炎症性肠病（IBD）的病理学中起着关键作用，其机制仍不完全清楚。在本研究中，我们发现E3连接酶F-box和WO重复结构域7（FBXW）在发炎肠道中的表达增加与人类疾病和小鼠模型中的IBD严重程度显著相关。骨髓Fbxw 7缺陷保护小鼠免受葡聚糖硫酸钠（OSS）或2，6，4-三硝基苯磺酸（TNBS）诱导的结肠炎。Fbxw 7缺陷导致结肠CX 3CR 1（hi）驻留巨噬细胞产生的趋化因子CCL 2和CCL 7减少，并减少了结肠炎影响的结肠组织中CX 3CR 1（int）促炎性MPh的积累。接受腺相关病毒-shFbxw 7（AAV-shFbxw 7）的小鼠显示出显著提高的存活率和结肠炎的缓解。机制筛选表明，FBXW 7抑制H3 K27 me 3修饰，并通过降解组蛋白赖氨酸N-甲基转移酶增强子zeste同源物2（EZH 2）促进CcI 2和CcI 7的表达。综上所述，我们的结果表明FBXW 7降解EZH 2并增加CX 3CR 1（hi）巨噬细胞中的CcI 2和CcI 7，从而促进CX 3CR 1（int）促炎性MPhs募集到结肠炎局部结肠组织中。靶向FBXW 7可能代表治疗肠道炎症的潜在治疗方法。
Resident and inflammatory mononuclear phagocytes (MPhs) with functional plasticity in the intestine are critically involved in the pathology of inflammatory bowel diseases (IBDs), the mechanism of which remains incompletely understood. In the present study, we found that increased expression of the E3 ligase F-box and WO repeat domain-containing 7 (FBXW) in the inflamed intestine was significantly correlated with IBD severity in both human diseases and in mouse models. Myeloid Fbxw7 deficiency protected mice from colitis induced by dextran sodium sulfate (OSS) or 2,6,4-trinitrobenzene sulfonic acid (TNBS). Fbxw7 deficiency resulted in decreased production of the chemokines CCL2 and CCL7 by colonic CX3CR1(hi) resident macrophages and reduced the accumulation of CX3CR1(int) proinflammatory MPhs in colitis-affected colon tissue. Mice that received adeno-associated virus-shFbxw7 (AAV-shFbxw7) showed significantly improved survival rates and alleviation of colitis. Mechanism screening demonstrated that FBXW7 suppressed H3K27me3 modification and promoted CcI2 and CcI7 expression via degradation of the histone-lysine N-methyltransferase enhancer of zeste homolog 2 (EZH2) in macrophages. Taken together, our results indicate that FBXW7 degrades EZH2 and increases CcI2 and CcI7 in CX3CR1(hi) macrophages, thereby promoting the recruitment of CX3CR1(int) proinflammatory MPhs into local colon tissues with colitis. Targeting FBXW7 might represent a potential therapeutic approach for the treatment of intestinal inflammation.