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SARI attenuates colon inflammation by promoting STAT1 degradation in intestinal epithelial cells.
Mucosal Immunology ( IF 8 ) Pub Date : 2019-06-10 , DOI: 10.1038/s41385-019-0178-9
Lei Dai 1 , Yi Liu 1 , Lin Cheng 1 , Huiling Wang 1 , Yi Lin 1 , Gang Shi 1 , Zhexu Dong 1 , Junshu Li 1 , Ping Fan 2 , Qinnan Wang 1 , Xiaolan Su 1 , Shuang Zhang 3 , Yang Yang 1 , Xun Hu 2 , Wei Huang 2 , Zongguang Zhou 4 , Dechao Yu 1 , Christopher Probert 5 , Yuquan Wei 1 , Hongxin Deng 1
Affiliation  

SARI functions as a suppressor of colon cancer and predicts survival of colon cancer patients, but its role in regulating colitis has not been characterized. Here we show that SARI-/- mice were highly susceptible to colitis, which was associated with enhanced macrophage infiltration and inflammatory cytokine production. Bone marrow reconstitution experiments demonstrated that disease susceptibility was not dependent on the deficiency of SARI in the immune compartment but on the protective role of SARI in the intestinal epithelial cells (IECs). Furthermore, SARI deficiency enhanced Chemokine (C-C motif) Ligand 2 (CCL2) production and knockout of CCR2 blocks the promoting role of SARI deficiency on colitis. Mechanistically, SARI directly targets and promotes signal transducer and activator of transcription 1 (STAT1) degradation in IECs, followed by persistent inactivation of the STAT1/CCL2 transcription complex. In summary, SARI attenuated colitis in mice by impairing colitis-dependent STAT1/CCL2 transcriptional activation in IECs and macrophages recruitment in colon tissue.

中文翻译:

SARI 通过促进肠上皮细胞中的 STAT1 降解来减轻结肠炎症。

SARI 作为结肠癌的抑制因子发挥作用并预测结肠癌患者的存活率,但其在调节结肠炎中的作用尚未得到表征。在这里,我们表明 SARI-/- 小鼠极易患结肠炎,这与增强的巨噬细胞浸润和炎性细胞因子的产生有关。骨髓重建实验表明,疾病易感性不依赖于免疫区室中 SARI 的缺乏,而是依赖于 SARI 在肠上皮细胞 (IEC) 中的保护作用。此外,SARI 缺陷增强了趋化因子(CC 基序)配体 2 (CCL2) 的产生和 CCR2 的敲除阻断了 SARI 缺陷对结肠炎的促进作用。从机制上讲,SARI 直接靶向并促进 IEC 中信号转导和转录激活因子 1 (STAT1) 的降解,随后是 STAT1/CCL2 转录复合物的持续失活。总之,SARI 通过破坏 IEC 中依赖于结肠炎的 STAT1/CCL2 转录激活和结肠组织中巨噬细胞的募集来减轻小鼠的结肠炎。
更新日期:2019-11-18
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