Sam68 contributes to intestinal inflammation in experimental and human colitis.
Sam68 contributes to intestinal inflammation in experimental and human colitis.
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DOI：
10.1007/s00018-021-03976-7
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Ramakrishnan P
中科院分区：
文献类型：
--
作者：
Goodman WA;Basavarajappa SC;Liu AR;Rodriguez FDS;Mathes T;Ramakrishnan P
Sam 68是一种RNA结合蛋白，在信号转导中具有接头作用。我们以前的工作确定了Sam 68的关键促炎和凋亡功能，位于TNF/TNFR 1和TLR 2/3/4通路的下游。最近的研究表明，类风湿性关节炎和溃疡性结肠炎（UC）患者的炎症组织中Sam 68升高，表明Sam 68有助于慢性炎症性疾病。在这里，我们假设Sam 68的缺失通过减少TNF相关的炎症信号传导而对体内实验性结肠炎具有保护作用。我们使用Sam 68基因敲除（KO）小鼠研究Sam 68在实验性结肠炎中的作用，包括其对三维肠道类器官培养物中TNF诱导的炎症基因表达的贡献。我们还研究了UC患者结肠组织中Sam 68和炎症基因的表达。与野生型对照相比，用DSS急性过程处理的Sam 68 KO小鼠表现出显著更少的体重减轻和组织病理学炎症，表明Sam 68有助于实验性结肠炎。骨髓移植显示造血细胞特异性Sam 68没有病理作用，表明非造血Sam 68驱动肠道炎症。基因表达分析表明，Sam 68缺陷减少了DSS处理小鼠结肠组织中促炎基因的表达，以及TNF处理的三维结肠类器官。我们还发现，炎症基因，如TNF，CCR 2，CSF 2，IL 33和CXCL 10，以及Sam 68蛋白，在UC患者的炎症结肠组织中上调。该报告将Sam 68确定为响应肠上皮损伤的重要炎症驱动因素，这表明靶向Sam 68可能有望治疗UC患者。
Sam68 is an RNA-binding protein with an adaptor role in signal transduction. Our previous work identified critical proinflammatory and apoptotic functions for Sam68, downstream of the TNF/TNFR1 and TLR2/3/4 pathways. Recent studies have shown elevated Sam68 in inflamed tissues from rheumatoid arthritis and ulcerative colitis (UC) patients, suggesting that Sam68 contributes to chronic inflammatory diseases. Here, we hypothesized that deletion of Sam68 is protective against experimental colitis in vivo, via reductions in TNF-associated inflammatory signaling. We used Sam68 knockout (KO) mice to study the role of Sam68 in experimental colitis, including its contributions to TNF-induced inflammatory gene expression in three-dimensional intestinal organoid cultures. We also studied the expression of Sam68 and inflammatory genes in colon tissues of UC patients. Sam68 KO mice treated with an acute course of DSS exhibited significantly less weight loss and histopathological inflammation compared to wild-type controls, suggesting that Sam68 contributes to experimental colitis. Bone marrow transplants showed no pathologic role for hematopoietic cell-specific Sam68, suggesting that non-hematopoietic Sam68 drives intestinal inflammation. Gene expression analyses showed that Sam68 deficiency reduced the expression of proinflammatory genes in colon tissues from DSS-treated mice, as well as TNF-treated three-dimensional colonic organoids. We also found that inflammatory genes, such as TNF, CCR2, CSF2, IL33 and CXCL10, as well as Sam68 protein, were upregulated in inflamed colon tissues of UC patients. This report identifies Sam68 as an important inflammatory driver in response to intestinal epithelial damage, suggesting that targeting Sam68 may hold promise to treat UC patients.
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DOI：
10.1073/pnas.1016814108
发表时间：
2010-12-14
影响因子：
11.1
作者：
Hu, Bo;Elinav, Eran;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
影响因子：
65.1
作者：
de Souza, Heitor S. P.;Fiocchi, Claudio;Iliopoulos, Dimitrios
通讯作者：
Iliopoulos, Dimitrios
影响因子：
29.7
作者：
Kaser A;Zeissig S;Blumberg RS
通讯作者：
Blumberg RS
影响因子：
5.8
作者：
de Jesus, Tristan James;Ramakrishnan, Parameswaran
通讯作者：
Ramakrishnan, Parameswaran
DOI：
10.1038/s41575-020-0354-0
发表时间：
2020-12
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
Goodman WA;Erkkila IP;Pizarro TT
通讯作者：
Pizarro TT