Kynurenine plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate-induced colitis in mice
Kynurenine plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate-induced colitis in mice
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DOI：
10.3748/wjg.v26.i9.918
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发表时间：
2020-03
影响因子：
4.3
通讯作者：
Chieko Tashita;Masato Hoshi;A. Hirata;K. Nakamoto;T. Ando;T. Hattori;Yasuko Yamamoto;H. Tezuka;H. Tomita;A. Hara;Kuniaki Saito
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作者：
Chieko Tashita;Masato Hoshi;A. Hirata;K. Nakamoto;T. Ando;T. Hattori;Yasuko Yamamoto;H. Tezuka;H. Tomita;A. Hara;Kuniaki Saito
背景炎症性肠病，如克罗恩病和溃疡性结肠炎，以慢性肠炎为特征，导致肠粘膜损伤。炎症性肠病引起粘膜T细胞反应的失调，尤其是CD4+T细胞的反应。在此之前，我们已经证明吲哚-2，3-双加氧酶在2，4，6-三硝基苯硫酸酯(TNBS)诱导的结肠炎中具有免疫抑制作用。尽管吲哚胺-2，3-双加氧酶通过改变局部色氨酸(Trp)和免疫调节色氨酸代谢产物的浓度来发挥免疫抑制作用，但Trp代谢产物及其相关酶在结肠炎过程中免疫调节的特异性变化尚不清楚。目的探讨犬尿氨酸3-单加氧酶(KMO)在TNBS诱导的结肠炎中的作用及色氨酸代谢产物在维持肠道内环境稳定中的作用。方法用TnBS诱导8周龄C57BL/6N背景的雄性−/−小鼠结肠炎。3天后，取结肠组织行苏木精-伊红染色进行组织学分级，免疫组织化学或免疫荧光染色检测KMO、细胞因子和免疫细胞。用定量RT-PCR检测炎症和抗炎细胞因子，用高效液相色谱法检测犬尿氨酸(Kyn)途径代谢产物。用流式细胞仪分析结肠固有层和肠系膜淋巴结的细胞比例。结果经TNBS诱导后，结肠单核巨噬细胞包括树突状细胞和巨噬细胞的KMO表达水平升高。值得注意的是，KMO缺乏减少了TNBS诱导的结肠炎，导致FOXP3+调节性T细胞的频率增加，并增加了抗炎细胞因子的基因和蛋白水平，包括转化生长因子-β和白介素10。结论KMO的缺失可能通过产生KYN而产生Foxp3+调节性T细胞，从而减轻TNBS诱导的结肠炎。因此，Kyn可能在结肠炎期间起到保护结肠的治疗作用。
BACKGROUND Inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis, is characterized by chronic intestinal inflammation leading to intestinal mucosal damage. Inflammatory bowel disease causes dysregulation of mucosal T cell responses, especially the responses of CD4+ T cells. Previously, we demonstrated that indoleamine-2,3-dioxygenase plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate (TNBS)-induced colitis. Although indoleamine-2,3-dioxygenase exerts immunosuppressive effects by altering the local concentration of tryptophan (Trp) and immunomodulatory Trp metabolites, the specific changes in immune regulation during colitis caused by Trp metabolites and its related enzymes remain unclear. AIM To investigate role of kynurenine 3-monooxygenase (KMO) in TNBS-induced colitis and involvement of Trp metabolites in maintenance of intestinal homeostasis. METHODS Colitis was induced in eight-week-old male KMO+/+ or KMO−/− mice of C57BL/6N background using TNBS. Three days later, the colon was used for hematoxylin-eosin staining for histological grading, immunohistochemical or immunofluorescence staining for KMO, cytokines, and immune cells. Inflammatory and anti-inflammatory cytokines were measured using quantitative RT-PCR, and kynurenine (Kyn) pathway metabolites were measured by high-performance liquid chromatography. The cell proportions of colonic lamina propria and mesenteric lymph nodes were analyzed by flow cytometry. RESULTS KMO expression levels in the colonic mononuclear phagocytes, including dendritic cells and macrophages increased upon TNBS induction. Notably, KMO deficiency reduced TNBS-induced colitis, resulting in an increased frequency of Foxp3+ regulatory T cells and increased mRNA and protein levels of anti-inflammatory cytokines, including transforming growth factor-β and interleukin-10. CONCLUSION Absence of KMO reduced TNBS-induced colitis via generation of Foxp3+ regulatory T cells by producing Kyn. Thus, Kyn may play a therapeutic role in colon protection during colitis.