Purinergic signaling during intestinal inflammation.
Purinergic signaling during intestinal inflammation.
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DOI：
10.1007/s00109-017-1545-1
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Robson SC
中科院分区：
文献类型：
--
作者：
Longhi MS;Moss A;Jiang ZG;Robson SC
炎症性肠病（IBD）是一种毁灭性的疾病，与遗传易感个体的肠道过度炎症有关，并可能由微生物生态失调引发。这种疾病明显使患者易患血栓形成倾向和慢性虚弱以及肠癌、淋巴癌和肝癌。需要开发新的治疗方法来重建IBD患者的长期免疫耐受性，而不会增加机会性感染和癌症的风险。异常的嘌呤能信号传导途径与血栓调节紊乱和免疫失调有关，如IBD和其他胃肠道/肝脏自身免疫性疾病的发病机制中所述。CD 39在内皮细胞或免疫细胞上的表达允许止血和免疫的稳态整合，这在IBD中被破坏。我们在这篇综述中的重点是在IBD的CD 39和相关NTPDases的功能的新方面。调节的CD 39活性允许清除细胞外核苷酸，维持P2受体的完整性和协调腺苷能信号传导反应。CD 39与CD 73一起作为树突细胞、骨髓细胞、T和B细胞的免疫抑制机制的组成部分。遗传遗传和免疫因子密切调节免疫细胞和释放微粒上CD 39的表达水平和磷酸水解活性。与T调节和抑制性T辅助细胞17型相关的嘌呤能机制调节IBD中的疾病活动，如可以在实验性结肠炎中建模的。最近的一个例子是，CD 39的上调依赖于芳香烃受体（AHR）的连接，与天然配体如胆红素和2-（1′ H-吲哚-3 ′-羰基）-噻唑-4-羧酸甲酯（ITE）一样。然而，CD 39表达减少和/或AHR信号传导功能障碍消除了免疫抑制性AHR配体的保护作用。这些因素也可以作为IBD疾病活动的生物标志物。在IBD中观察到的血栓形成、炎症和免疫紊乱的加剧似乎与异常的嘌呤能信号传导有关。通过细胞因子或AHR配体增强CD 39外核苷酸酶生物活性的治疗策略的持续开发为IBD中的血栓形成倾向、紊乱性炎症和异常免疫反应性的管理提供了希望。
Inflammatory bowel disease (IBD) is a devastating disease that is associated with excessive inflammation in the intestinal tract in genetically susceptible individuals and potentially triggered by microbial dysbiosis. This illness markedly predisposes patients to thrombophilia and chronic debility as well as bowel, lymphatic, and liver cancers. Development of new therapies is needed to re-establish long-term immune tolerance in IBD patients without increasing the risk of opportunistic infections and cancer. Aberrant purinergic signaling pathways have been implicated in disordered thromboregulation and immune dysregulation, as noted in the pathogenesis of IBD and other gastrointestinal/hepatic autoimmune diseases. Expression of CD39 on endothelial or immune cells allows for homeostatic integration of hemostasis and immunity, which are disrupted in IBD. Our focus in this review is on novel aspects of the functions of CD39 and related NTPDases in IBD. Regulated CD39 activity allows for scavenging of extracellular nucleotides, the maintenance of P2-receptor integrity and coordination of adenosinergic signaling responses. CD39 together with CD73, serves as an integral component of the immunosuppressive machinery of dendritic cells, myeloid cells, T and B cells. Genetic inheritance and environental factors closely regulate the levels of expression and phosphohydrolytic activity of CD39, both on immune cells and released microparticles. Purinergic mechanisms associated with T regulatory and supressor T helper type 17 cells modulate disease activity in IBD, as can be modeled in experimental colitis. As a recent example, upregulation of CD39 is dependent upon ligation of the aryl hydrocarbon receptor (AHR), as with natural ligands such as bilirubin and 2-(1′ H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Decreased expression of CD39 and/or dysfunctional AHR signaling, however, abrogates the protective effects of immunosuppressive AHR ligands. These factors could also serve as biomarkers of disease activity in IBD. Heightened thrombosis, inflammation, and immune disturbances as seen in IBD appear to be associated with aberrant purinergic signaling. Ongoing development of therapeutic strategies augmenting CD39 ectonucleotidase bioactivity via cytokines or AHR ligands offers promise for management of thrombophilia, disordered inflammation, and aberrant immune reactivity in IBD.
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影响因子：
30.5
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