Indole-3-Pyruvic Acid, an Aryl Hydrocarbon Receptor Activator, Suppresses Experimental Colitis in Mice
Indole-3-Pyruvic Acid, an Aryl Hydrocarbon Receptor Activator, Suppresses Experimental Colitis in Mice
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DOI：
10.4049/jimmunol.1701734
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发表时间：
2018-12-15
影响因子：
4.4
通讯作者：
Takayama, Yoshiharu
中科院分区：
文献类型：
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作者：
Aoki, Reiji;Aoki-Yoshida, Ayako;Takayama, Yoshiharu
芳基烃受体（AHR）激动剂是有前途的免疫调节剂，有可能维持免疫耐受。在这项研究中，我们检测了吲哚-3-丙酮酸 (IPA) 激活 AHR 的能力，IPA 是微生物群衍生的 AHR 激动剂的主要前体，也是 AHR 的前体。还在结肠炎小鼠模型中评估了 IPA 的抗炎作用，并与其他芳香族丙酮酸（苯基丙酮酸和 4-羟基苯基丙酮酸）进行比较。其中，IPA在体外和体内表现出最强的激活AHR的能力，并且只有IPA在实验性结肠炎模型中改善慢性炎症。 IPA 减弱了结肠中编码 Th1 细胞因子的基因的表达并增强了 Il-10 基因的表达。在T细胞介导的结肠炎模型中，口服IPA可降低结肠固有层中IFN-γ(+) IL-10(-) CD4(+) T细胞的频率并增加IFN-γ(-) IL-10(+) CD4(+) T细胞的频率。 IPA在体外直接促进1型调节性T细胞的分化。此外，IPA给药减弱了肠系膜淋巴结（MLN）中的树突状细胞（DC）诱导产生IFN-γ的T细胞的能力，增加了MLN中CD103（+）CD11b（-）DC的频率，并降低了CD103（-）CD11b（+）DC的频率。 MLN CD103(+) CD11b(-) DC 的过继转移显着改善了结肠炎症的严重程度。 AHR拮抗剂治疗抑制IPA诱导的1型调节性T细胞分化和IPA诱导的CD103(+) CD11b(-) DCs增加，并减弱IPA的抗炎作用。这些发现表明，IPA 通过激活 AHR 有效预防结肠中的慢性炎症。
Aryl hydrocarbon receptor (AHR) agonists are promising immunomodulators that potentially maintain immune tolerance. In this study, we examined the ability of indole-3-pyruvic acid (IPA), a major precursor of microbiota-derived AHR agonists and a proagonist of AHR, to activate AHR. The anti-inflammatory effects of IPA were also evaluated in a mouse model of colitis in comparison with other aromatic pyruvic acids (phenylpyruvic acid and 4-hydroxyphenylpyruvic acid). Among them, IPA showed the strongest ability to activate AHR in vitro and in vivo, and only IPA improved chronic inflammation in an experimental colitis model. IPA attenuated the expression of genes encoding Th1 cytokines and enhanced Il-10 gene expression in the colon. Oral administration of IPA decreased the frequency of IFN-gamma(+) IL-10(-) CD4(+) T cells and increased that of IFN-gamma(-) IL-10(+) CD4(+) T cells in the colon lamina propria in a T cell-mediated colitis model. IPA directly promoted the differentiation of type 1 regulatory T cells in vitro. Furthermore, IPA administration attenuated the ability of dendritic cells (DCs) in the mesenteric lymph nodes (MLN) to induce IFN-gamma-producing T cells, increased the frequency of CD103(+) CD11b(-) DCs, and decreased the frequency of CD103(-) CD11b(+) DCs in the MLN. Adoptive transfer of MLN CD103(+) CD11b(-) DCs significantly improved the severity of colon inflammation. Treatment with an AHR antagonist inhibited IPA-induced differentiation of type 1 regulatory T cells and the IPA-induced increase in CD103(+) CD11b(-) DCs and attenuated the anti-inflammatory effect of IPA. These findings suggest that IPA potently prevents chronic inflammation in the colon by activating AHR.