A Novel Role for TL1A/DR3 in Protection against Intestinal Injury and Infection.
A Novel Role for TL1A/DR3 in Protection against Intestinal Injury and Infection.
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TL1A/DR3在防御肠道损伤和感染中的新作用。
DOI：
10.4049/jimmunol.1502466
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发表时间：
2016-07-01
期刊：
影响因子：
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通讯作者：
Cominelli F
中科院分区：
文献类型：
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作者：
Jia LG;Bamias G;Arseneau KO;Burkly LC;Wang EC;Gruszka D;Pizarro TT;Cominelli F
肿瘤坏死因子（TNF）样细胞因子1A（TL 1A）在抗原呈递细胞上表达，并向携带其功能性受体死亡受体3（DR 3）的活化淋巴细胞提供共刺激信号。TL 1A/DR 3信号转导参与人类和实验性炎症性肠病（IBD）的发病机制。在本研究中，我们研究了这种细胞因子/受体对在急性肠损伤/修复途径中的作用。我们证明了完整的DR 3信号可以保护小鼠免受急性DSS结肠炎的影响，因为DR 3 −/−小鼠表现出更严重的粘膜炎症和更高的死亡率。DR 3 −/−小鼠在应对急性粘膜损伤时维持足够数量的CD 4 + CD 25 + Foxp 3 + T调节细胞（T细胞）的能力受损。这种免疫调节缺陷导致效应物促炎途径的非特异性上调，这对于Th 17免疫表型最为突出。TL 1A −/−小鼠同样更容易患DSS结肠炎，尽管与DR 3 −/−小鼠相比，没有死亡率和动力学延迟，并且还显示出显著减少的TdR数量。鼠伤寒沙门氏菌感染DR 3 −/−小鼠与微生物清除缺陷和细菌负荷升高相关。总之，我们的研究结果表明，TL 1A/DR 3轴在急性肠损伤/修复期间调节粘膜稳态中具有新的保护作用，这与其在慢性肠道炎症期间的已知致病功能形成对比。
Tumor necrosis factor (TNF)-like cytokine 1A (TL1A) is expressed on antigen presenting cells and provides co-stimulatory signals to activated lymphocytes that bear its functional receptor, death receptor 3 (DR3). TL1A/DR3 signaling is involved in the pathogenesis of human and experimental inflammatory bowel disease (IBD). In the present study, we investigated the role of this cytokine/receptor pair in acute intestinal injury/repair pathways. We demonstrate that intact DR3 signaling protected mice from acute DSS colitis, as DR3−/− mice showed more severe mucosal inflammation and increased mortality. DR3−/− mice were compromised in their ability to maintain adequate numbers of CD4+CD25+Foxp3+ T regulatory cells (Tregs) in response to acute mucosal damage. This defect in immune regulation led to a non-specific upregulation of effector pro-inflammatory pathways, which was most prominent for the Th17 immunophenotype. TL1A−/− mice were similarly more susceptible to DSS colitis, although without mortality and with delayed kinetics compared to DR3−/− mice, and also displayed significantly reduced numbers of Tregs. Infection of DR3−/− mice with Salmonella typhimurium was associated with defective microbial clearance and elevated bacterial load. Taken together, our findings indicate a novel protective role for the TL1A/DR3 axis in the regulation of mucosal homeostasis during acute intestinal injury/repair, which contrasts with its known pathogenic function during chronic intestinal inflammation.