Intestinal Epithelial TBK1 Prevents Differentiation of T-helper 17 Cells and Tumorigenesis in Mice.
Intestinal Epithelial TBK1 Prevents Differentiation of T-helper 17 Cells and Tumorigenesis in Mice.
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肠上皮TBK1可防止T甘油病17细胞的分化和小鼠的肿瘤发生。
DOI：
10.1053/j.gastro.2020.07.047
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发表时间：
2020-11
期刊：
影响因子：
29.4
通讯作者：
Sun SC
中科院分区：
文献类型：
--
作者：
Yang JY;Jie Z;Mathews A;Zhou X;Li Y;Gu M;Xie X;Ko CJ;Cheng X;Qi Y;Estrella JS;Wang J;Sun SC
肠上皮细胞（IECs）调节肠道免疫细胞，特别是辅助性t - 17 （Th17）细胞的发育。这一过程的放松会通过未知的机制导致肠道炎症和肿瘤发生。TANK-binding kinase 1 （TBK1）在先天免疫系统中由IECs和细胞表达。我们研究了TBK1在小鼠肠道免疫反应和肿瘤发生中的作用。我们对野生型小鼠、Tbk1条件性破坏小鼠（Tbk1IEC-KO）、Tbk1IEC-KO小鼠与ApcMin/+小鼠杂交、Mt - / -小鼠与ApcMin/+小鼠杂交进行了研究。部分小鼠腹腔注射抗白细胞介素17 （IL17）或IL1B的中和抗体。收集小鼠肠组织，进行组织学分析，检测腺瘤和Th17细胞的数量，real-time PCR检测炎症因子的表达。从野生型和Tbk1IEC-KO小鼠中分离iec，用脂多糖刺激，与骨髓源性巨噬细胞共培养，并通过RNA测序和生化分析进行分析。与ApcMin/+Tbk1WT小鼠相比，ApcMin/+Tbk1IEC-KO小鼠肠息肉数量和大小明显增加，固有层Th17细胞明显增多。在ApcMin/+Tbk1IEC-KO小鼠中，抗IL17抗体的使用减少了肠道息肉的数量，与ApcMin/+Tbk1WT小鼠相同。在培养中，tbk1缺陷IECs促进巨噬细胞表达IL1B，从而诱导naïve CD4+ T细胞向Th17细胞分化。RNA测序分析显示，tbk1缺失的IECs增加了金属硫蛋白1 （MT1）的表达，MT1是一种促进肠道炎症的免疫调节剂。与ApcMin/+Mt+/+小鼠相比，ApcMin/+Mt - / -小鼠的肠道组织中Th17细胞数量明显减少，息肉数量明显减少。对癌症基因组图谱中结直肠肿瘤的分析发现，高水平MT1和IL17 mrna的结直肠肿瘤与患者生存时间缩短相关。IECs表达TBK1可抑制MT1的表达，抑制巨噬细胞表达IL1B和Th17细胞的分化，从而防止炎症和肿瘤发生。阻断这一途径的策略可能会在结直肠肿瘤发生中得到发展。
Intestinal epithelial cells (IECs) regulate intestinal immune cells, particularly development of T-helper 17 (Th17) cells. Deregulation of this process leads to intestinal inflammation and tumorigenesis, via unknown mechanisms. TANK-binding kinase 1 (TBK1) is expressed by IECs and cells in the innate immune system. We studied the functions of TBK1 in the intestinal immune response and tumorigenesis in mice. We performed studies of wild-type mice, mice with conditional disruption of Tbk1 (Tbk1IEC-KO), Tbk1IEC-KO mice crossed with ApcMin/+ mice, and Mt−/− mice crossed with ApcMin/+ mice. Some mice were given intraperitoneal injections of a neutralizing antibody against interleukin 17 (IL17) or IL1B. Intestine tissues were collected from mice and analyzed by histology, for numbers of adenomas and Th17 cells, and expression of inflammatory cytokines by real-time PCR. IECs were isolated from wild-type and Tbk1IEC-KO mice, stimulated with lipopolysaccharide, co-cultured for with bone marrow-derived macrophages, and analyzed by RNA sequencing and biochemical analyses. Compared to ApcMin/+Tbk1WT mice, ApcMin/+Tbk1IEC-KO mice had significant increases in number and size of intestinal polyps, and significantly more Th17 cells in lamina propria. Administration of an antibody against IL17 reduced the number of intestinal polyps in ApcMin/+Tbk1IEC-KO mice to that observed in ApcMin/+Tbk1WT mice. In culture, TBK1-deficient IECs promoted expression of IL1B by macrophages, which induced differentiation of naïve CD4+ T cells into Th17 cells. RNA sequencing analysis revealed that the TBK1-deficient IECs had increased expression of metallothionein 1 (MT1), an immune regulator that promotes intestinal inflammation. Intestine tissues from ApcMin/+Mt−/− mice had significant fewer Th17 cells than ApcMin/+Mt+/+ mice, and a significantly lower number of polyps. Analyses of colorectal tumors in the Cancer Genome Atlas found colorectal tumors with high levels of MT1 and IL17 mRNAs to be associated with reduced survival times of patients. Expression of TBK1 by IECs suppresses expression of MT1 and prevents expression of IL1B by macrophages and differentiation of Th17 cells, to prevent inflammation and tumorigenesis. Strategies to block this pathway might be developed for colorectal tumorigenesis.
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DOI：
10.1038/ismej.2012.8
发表时间：
2012-08
期刊：
The ISME journal
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1016/j.bbrc.2011.11.031
发表时间：
2011-12-16
影响因子：
3.1
作者：
Devisscher, Lindsey;Hindryckx, Pieter;Laukens, Debby
通讯作者：
Laukens, Debby
影响因子：
64.5
作者：
Chien, Yuchen;Kim, Sungchan;White, Michael A.
通讯作者：
White, Michael A.
影响因子：
4.8
作者：
Clark, Kristopher;Plater, Lorna;Cohen, Philip
通讯作者：
Cohen, Philip
影响因子：
64.5
作者：
Chung H;Pamp SJ;Hill JA;Surana NK;Edelman SM;Troy EB;Reading NC;Villablanca EJ;Wang S;Mora JR;Umesaki Y;Mathis D;Benoist C;Relman DA;Kasper DL
通讯作者：
Kasper DL