Targeted Inhibition of Serotonin Type 7 (5-HT7) Receptor Function Modulates Immune Responses and Reduces the Severity of Intestinal Inflammation
Targeted Inhibition of Serotonin Type 7 (5-HT7) Receptor Function Modulates Immune Responses and Reduces the Severity of Intestinal Inflammation
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DOI：
10.4049/jimmunol.1201887
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发表时间：
2013-05-01
影响因子：
4.4
通讯作者：
Khan, Waliul I.
中科院分区：
文献类型：
--
作者：
Kim, Janice J.;Bridle, Byram W.;Khan, Waliul I.
从感染性急性肠炎或结肠炎到炎症性肠病的粘液炎性炎症伴随着肠道中5-羟色胺（5-羟色胺[5-HT]）含量的改变。最近，我们已经确定了5-HT在实验性结肠炎的发病机制中的重要作用。5-HT 7型（5-HT 7）受体是5-HT受体家族中最近鉴定的成员之一，并且树突状细胞表达该受体。在这项研究中，我们研究了阻断5-HT 7受体信号传导在实验性结肠炎中的作用，以期开发出一种改进的肠道炎症性疾病的治疗策略。在用选择性5-HT 7受体拮抗剂SB-269970处理的小鼠中，以及在缺乏5-HT 7受体（5-HT 7-/-）的小鼠和用从5-HT 7-/-小鼠收获的骨髓细胞重建的辐照野生型小鼠中，用葡聚糖硫酸钠（DSS）或二硝基苯磺酸（DNBS）诱导结肠炎。用SB-269970抑制5-HT 7受体信号传导可改善DSS诱导的急性和慢性结肠炎。与DSS后溶媒给药小鼠相比，SB-269970给药导致临床疾病、组织学损伤和促炎细胞因子水平降低。与DSS结肠炎后的对照小鼠相比，5-HT 7-/-小鼠和用来自5-HT 7-/-小鼠的骨髓细胞重建的小鼠的结肠炎严重程度显著降低。5-HT 7-/-小鼠也具有显著减少的DNBS诱导的结肠炎。这些观察结果为我们提供了关于5-HT 7受体在肠道免疫反应和炎症中的关键作用的新信息，并强调了靶向该受体以减轻肠道炎症性疾病（如炎症性肠病）严重程度的潜在益处。免疫学杂志，2013，190：4795-4804。
Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammatory bowel disease is accompanied by alteration in serotonin (5-hydroxytryptamine [5-HT]) content in the gut. Recently, we have identified an important role of 5-HT in the pathogenesis of experimental colitis. 5-HT type 7 (5-HT7) receptor is one of the most recently identified members of the 5-HT receptor family, and dendritic cells express this receptor. In this study, we investigated the effect of blocking 5-HT7 receptor signaling in experimental colitis with a view to develop an improved therapeutic strategy in intestinal inflammatory disorders. Colitis was induced with dextran sulfate sodium (DSS) or dinitrobenzene sulfonic acid (DNBS) in mice treated with selective 5-HT7 receptor antagonist SB-269970, as well as in mice lacking 5-HT7 receptor (5-HT7-/-) and irradiated wild-type mice reconstituted with bone marrow cells harvested from 5-HT7-/- mice. Inhibition of 5-HT7 receptor signaling with SB-269970 ameliorated both acute and chronic colitis induced by DSS. Treatment with SB-269970 resulted in lower clinical disease, histological damage, and proinflammatory cytokine levels compared with vehicle-treated mice post-DSS. Colitis severity was significantly lower in 5-HT7-/- mice and in mice reconstituted with bone marrow cells from 5-HT7-/- mice compared with control mice after DSS colitis. 5-HT7-/- mice also had significantly reduced DNBS-induced colitis. These observations provide us with novel information on the critical role of the 5-HT7 receptor in immune response and inflammation in the gut, and highlight the potential benefit of targeting this receptor to alleviate the severity of intestinal inflammatory disorders such as inflammatory bowel disease. The Journal of Immunology, 2013, 190: 4795-4804.