Pyrin Inflammasome Regulates Tight Junction Integrity to Restrict Colitis and Tumorigenesis.
Pyrin Inflammasome Regulates Tight Junction Integrity to Restrict Colitis and Tumorigenesis.
复制标题
DOI：
10.1053/j.gastro.2017.11.276
复制
发表时间：
2018-03
期刊：
影响因子：
29.4
通讯作者：
Kanneganti TD
中科院分区：
文献类型：
--
作者：
Sharma D;Malik A;Guy CS;Karki R;Vogel P;Kanneganti TD
炎症性肠病（IBD）增加结直肠癌的风险。地中海热基因（MEFV或pyrin）的突变与遗传性自身炎性疾病和严重IBD相关。在IBD患者的结肠活检组织中，MEFV（一种启动炎性体复合物组装的传感器蛋白）的表达增加。我们研究了pyrin在小鼠肠道内稳态中的作用。Mefv−/−小鼠和C57/BL 6小鼠（对照组）被给予氧化偶氮甲烷，然后给予多轮葡聚糖硫酸钠（DSS）以诱导结肠炎和肿瘤发生。在一些实验中，Mefv−/−小鼠在DSS给药期间注射重组白细胞介素18（rIL 18）或盐水（对照）。在结肠炎发展期间的不同时间点收集结肠组织，并通过组织学、免疫组织化学、免疫印迹或ELISA（以测量细胞因子）进行分析。收集脾和肠系膜淋巴结，处理并通过流式细胞术分析。通过灌胃荧光葡聚糖和定量血清水平来测量结肠炎小鼠的结肠上皮通透性。MEFV在对照小鼠结肠中表达，并且在慢性和急性炎症期间表达增加;在结肠肿瘤和邻近非肿瘤组织中检测到高水平。Mefv−/−小鼠比对照小鼠发生更严重的结肠炎，上皮增生程度更大，肿瘤负荷更大。在结肠炎诱导后，Mefv−/−小鼠结肠中炎性细胞因子（IL 6）和趋化因子的水平显著高于对照小鼠，而依赖于炎性小体成熟和释放的IL 18水平在Mefv−/−小鼠结肠中显著较低。与对照小鼠相比，给予DSS后，Mefv−/−小鼠的上皮通透性增加，细胞间连接的紧密连接蛋白occludin和claudin-2丢失。STAT 3在Mefv−/−的炎症结肠组织中被激活（磷酸化），与对照小鼠的结肠相比，Mefv−/−的干细胞标志物（OLFM 4，BMI 1和MSI 1）的表达也增加。给予Mefv−/−小鼠rIL 18可降低上皮通透性、肠道炎症、结肠炎严重程度和结肠肿瘤发生。在DSS诱导的结肠炎小鼠的研究中，我们发现pyrin（MEFV）是炎性小体激活和IL 18成熟所必需的，其促进肠屏障完整性并预防结肠炎症和肿瘤发生。增加MEFV或IL 18活性的策略可能被开发用于治疗IBD和预防结肠炎相关的肿瘤发生。
Inflammatory bowel diseases (IBD) increase risk for colorectal cancer. Mutations in the Mediterranean fever gene (MEFV or pyrin) are associated with hereditary autoinflammatory disease and severe IBD. Expression of MEFV, a sensor protein that the initiates assembly of the inflammasome complex, is increased in colon biopsies from patients with IBD. We investigated the role of pyrin in intestinal homeostasis in mice. Mefv−/− mice and C57/BL6 mice (controls) were given azoxymethane followed by multiple rounds of dextran sodium sulfate (DSS) to induce colitis and tumorigenesis. In some experiments, Mefv−/− mice were given injections of recombinant interleukin 18 (rIL18) or saline (control) during DSS administration. Colon tissues were collected at different time points during colitis development and analyzed by histology, immunohistochemistry, immunoblots, or ELISAs (to measure cytokines). Spleen and mesenteric lymph node were collected, processed, and analyzed by flow cytometry. Colon epithelial permeability was measured in mice with colitis by gavage of fluorescent dextran and quantification of serum levels. MEFV was expressed in colons of control mice and expression increased during chronic and acute inflammation; high levels were detected in colon tumor and adjacent non-tumor tissues. Mefv−/− mice developed more severe colitis than control mice, with a greater extent of epithelial hyperplasia and a larger tumor burden. Levels of inflammatory cytokines (IL6) and chemokines were significantly higher in colons of Mefv−/− mice than control mice following colitis induction, whereas the level IL18, which depends on the inflammasome for maturation and release, was significantly lower in colons of Mefv−/− mice. Mefv−/− mice had increased epithelial permeability following administration of DSS than control mice, and loss of the tight junction proteins occludin and claudin-2 from intercellular junctions. STAT3 was activated (phosphorylated) in inflamed colon tissues from Mefv−/−, which also had increased expression of stem cell markers (OLFM4, BMI1, and MSI1) compared to colons from control mice. Administration of rIL18 to Mefv−/− mice reduced epithelial permeability, intestinal inflammation, the severity of colitis, and colon tumorigenesis. In studies of mice with DSS-induced colitis, we found that pyrin (MEFV) is required for inflammasome activation and IL18 maturation, which promote intestinal barrier integrity and prevent colon inflammation and tumorigenesis. Strategies to increase activity of MEFV or IL18 might be developed for treatment of IBD and prevention of colitis-associated tumorigenesis.
登录
查看更多内容
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：
3.1
作者：
Gaudio, E;Taddei, G;Caprilli, R
通讯作者：
Caprilli, R
DOI：
10.1084/jem.20100050
发表时间：
2010-05-10
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Allen IC;TeKippe EM;Woodford RM;Uronis JM;Holl EK;Rogers AB;Herfarth HH;Jobin C;Ting JP
通讯作者：
Ting JP
影响因子：
24.5
作者：
Arrieta, M. C.;Madsen, K.;Doyle, J.;Meddings, J.
通讯作者：
Meddings, J.
DOI：
10.4049/jimmunol.1102272
发表时间：
2012-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Gavrilin MA;Abdelaziz DH;Mostafa M;Abdulrahman BA;Grandhi J;Akhter A;Abu Khweek A;Aubert DF;Valvano MA;Wewers MD;Amer AO
通讯作者：
Amer AO