IL-22 Upregulates Epithelial Claudin-2 to Drive Diarrhea and Enteric Pathogen Clearance.
IL-22 Upregulates Epithelial Claudin-2 to Drive Diarrhea and Enteric Pathogen Clearance.
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DOI：
10.1016/j.chom.2017.05.009
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发表时间：
2017-06-14
影响因子：
30.3
通讯作者：
Turner JR
中科院分区：
文献类型：
--
作者：
Tsai PY;Zhang B;He WQ;Zha JM;Odenwald MA;Singh G;Tamura A;Shen L;Sailer A;Yeruva S;Kuo WT;Fu YX;Tsukita S;Turner JR
腹泻是宿主对肠道病原体的反应，但其对发病机制的影响仍不清楚。通过用附着和消退细菌啮齿类柠檬酸杆菌感染小鼠，我们确定了腹泻和肠道屏障丧失对宿主防御的机制和贡献。增加的渗透性发生在感染后2天内，与IL-22依赖性上皮紧密连接蛋白claudin-2的上调相一致。渗透性增加仅限于小分子，正如对由claudin-2形成的细胞旁水和Na+通道所预期的那样。相对于野生型，claudin-2缺陷小鼠经历了严重的疾病，包括增加的粘膜定植由C。啮齿动物，延长病原体脱落，夸大的细胞因子反应和更大的组织损伤。相反，转基因claudin-2过表达降低了疾病的严重程度。化学诱导的渗透性腹泻降低了结肠炎的严重程度，C。在claudin-2缺陷但非转基因小鼠中的啮齿类动物负担，证明claudin-2介导的保护是水流出增强的结果。因此，IL-22诱导的密蛋白-2上调驱动腹泻和病原体清除。腹泻在肠道感染中很常见，但这是否反映了疾病进展或宿主防御尚不清楚。利用C.在啮齿动物模型中，Tsai等人显示腹泻对于病原体清除是关键的，并且证明腹泻发展需要密蛋白-2上调，其增加紧密连接对Na+和水的渗透性。
Diarrhea is a host response to enteric pathogens, but its impact on pathogenesis remains poorly defined. By infecting mice with the attaching and effacing bacteria Citrobacter rodentium, we defined the mechanisms and contributions of diarrhea and intestinal barrier loss to host defense. Increased permeability occurred within 2 days of infection and coincided with IL-22-dependent upregulation of the epithelial tight junction protein claudin-2. Permeability increases were limited to small molecules, as expected for the paracellular water and Na+ channel formed by claudin-2. Relative to wildtype, claudin-2-deficient mice experienced severe disease, including increased mucosal colonization by C. rodentium, prolonged pathogen shedding, exaggerated cytokine responses, and greater tissue injury. Conversely, transgenic claudin-2 overexpression reduced disease severity. Chemically-induced osmotic diarrhea reduced colitis severity and C. rodentium burden in claudin-2 deficient, but not transgenic, mice, demonstrating that claudin-2-mediated protection is the result of enhanced water efflux. Thus, IL-22-induced claudin-2 upregulation drives diarrhea and pathogen clearance. Diarrhea is common in enteric infection, but whether this reflects disease progression or host defense is unknown. Using the C. rodentium model, Tsai et al. show that diarrhea is critical to pathogen clearance and demonstrate that diarrhea development requires claudin-2 upregulation that increases tight junction permeability to Na+ and water.
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影响因子：
32.4
作者：
Basu R;O'Quinn DB;Silberger DJ;Schoeb TR;Fouser L;Ouyang W;Hatton RD;Weaver CT
通讯作者：
Weaver CT
上皮内膜IKKα表达调节3组先天淋巴样细胞反应和抗菌免疫。
DOI：
10.1084/jem.20141831
发表时间：
2015-09-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Giacomin PR;Moy RH;Noti M;Osborne LC;Siracusa MC;Alenghat T;Liu B;McCorkell KA;Troy AE;Rak GD;Hu Y;May MJ;Ma HL;Fouser LA;Sonnenberg GF;Artis D
通讯作者：
Artis D
DOI：
10.4049/jimmunol.1201373
发表时间：
2013-02-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Rosen MJ;Chaturvedi R;Washington MK;Kuhnhein LA;Moore PD;Coggeshall SS;McDonough EM;Weitkamp JH;Singh AB;Coburn LA;Williams CS;Yan F;Van Kaer L;Peebles RS Jr;Wilson KT
通讯作者：
Wilson KT
DOI：
10.1084/jem.20082683
发表时间：
2009-07-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Pickert G;Neufert C;Leppkes M;Zheng Y;Wittkopf N;Warntjen M;Lehr HA;Hirth S;Weigmann B;Wirtz S;Ouyang W;Neurath MF;Becker C
通讯作者：
Becker C
影响因子：
3.4
作者：
Guttman, JA;Li, YL;Finlay, BB
通讯作者：
Finlay, BB