SARI attenuates colon inflammation by promoting STAT1 degradation in intestinal epithelial cells
SARI attenuates colon inflammation by promoting STAT1 degradation in intestinal epithelial cells
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SARI 通过促进肠上皮细胞中 STAT1 降解来减轻结肠炎症
DOI：
10.1038/s41385-019-0178-9
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发表时间：
2019-09-01
影响因子：
8
通讯作者：
Deng, Hongxin
中科院分区：
文献类型：
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作者：
Dai, Lei;Liu, Yi;Deng, Hongxin
SARI具有抑制结肠癌的作用，并预测结肠癌患者的生存，但其在调节结肠炎中的作用尚未确定。在这里，我们表明SARI(-/-)小鼠对结肠炎高度易感，这与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，疾病的易感性并不取决于免疫小室中sARI的缺陷，而是取决于sARI对肠上皮细胞(IECS)的保护作用。此外，莎莉缺乏促进趋化因子(C-C基序)配体2(CCL2)的产生和CCR2的敲除阻断了莎莉缺乏对结肠炎的促进作用。在机制上，SARI直接靶向并促进IECS中信号转导和转录激活因子1(STAT1)的降解，继而持续失活STAT1/CCL2转录复合体。综上所述，sari通过抑制结肠炎依赖的IECs中STAT1/CCL2的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。
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.