Serotonin/5-hydroxytryptamine-3 receptors promote colonic inflammation via activation of substance P/neurokinin-1 receptors in dextran sulphate sodium-induced murine colitis
Serotonin/5-hydroxytryptamine-3 receptors promote colonic inflammation via activation of substance P/neurokinin-1 receptors in dextran sulphate sodium-induced murine colitis
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右旋糖酐硫酸钠诱导的小鼠结肠炎中血清素/5-羟色胺-3受体通过激活P物质/神经激肽-1受体促进结肠炎症
DOI：
10.1111/bph.13482
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Kato S.
中科院分区：
文献类型：
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作者：
Utsumi D;Matsumoto K;Amagase K;Horie S;Kato S.
背景和目的5-羟色胺(5-羟色胺)直接或通过肠神经调节多种生理功能。本研究探讨了内源性5-羟色胺和5-羟色胺受体在结肠炎发病机制中的作用，特别是与P物质(SP)和神经激肽-1(NK1)受体的关系。结果每日给予雷莫司琼和恩丹西酮(5-HT3拮抗剂)可剂量依赖性地减轻DSS诱导的大鼠结肠炎的严重程度，并上调炎症介质的表达。免疫组织化学分析显示，正常结肠组织5-HT3受体主要表达于囊泡ACh转运体阳性胆碱能神经纤维。DSS可增加5-HT3受体和SP双阳性神经纤维的数目，但不增加5-HT3受体和囊泡ACh转运体双阳性神经纤维的数目。DSS可增加结肠SP水平和SP阳性神经纤维；这些反应可被雷莫司琼减弱。NK1拮抗剂Approant可减轻DSS诱导的结肠炎和炎症介质的上调。免疫组织化学研究进一步显示，DSS治疗后CD11b阳性细胞NK1受体表达明显增加。结论与意义5-羟色胺/5-HT3受体和SP/NK1受体通路在结肠炎症中起致病作用。5-羟色胺通过5-HT3受体上调炎症介质，促进结肠炎症。这些作用可能通过5-HT3受体阳性神经纤维释放的SP激活巨噬细胞NK1受体而进一步介导。
Background and Purpose5‐HT (serotonin) regulates various physiological functions, both directly and via enteric neurons. The present study investigated the role of endogenous 5‐HT and 5‐HT3receptors in the pathogenic mechanisms involved in colonic inflammation, especially in relation to substance P (SP) and the neurokinin‐1 (NK1) receptor.Experimental ApproachThe effects of 5‐HT3and NK1receptor antagonists were examined in dextran sulphate sodium (DSS)‐induced colitis in mice. Inflammatory mediator expression and the distribution of 5‐HT3and NK1receptors were also determined.Key ResultsDaily administration of ramosetron and ondansetron (5‐HT3antagonists) dose‐dependently attenuated the severity of DSS‐induced colitis and up‐regulation of inflammatory mediator expression. Immunohistochemical analysis showed 5‐HT3receptors are mainly expressed in vesicular ACh transporter‐positive cholinergic nerve fibres in normal colon. DSS increased the number of colonic nerve fibres that were double positive for 5‐HT3receptors and SP but not of those that were double positive for 5‐HT3receptors and vesicular ACh transporter. DSS increased colonic SP levels and SP‐positive nerve fibres; these responses were attenuated by ramosetron. DSS‐induced colitis and up‐regulation of inflammatory mediators were attenuated by aprepitant, an NK1antagonist. Immunohistochemical studies further revealed that DSS treatment markedly increased NK1receptor expression in CD11b‐positive cells.Conclusions and ImplicationsThese findings indicate that the 5‐HT/5‐HT3receptor and SP/NK1receptor pathways play pathogenic roles in colonic inflammation. 5‐HT acts via 5‐HT3receptors to up‐regulate inflammatory mediators and promote colonic inflammation. These effects may be further mediated by activation of macrophage NK1receptors via SP released from 5‐HT3receptor‐positive nerve fibres.