黏膜胰岛素受体的激活通过促进组织驻留记忆 T 细胞分化来加重肠道炎症，这种作用是通过 EZH2 实现的。

Activation of mucosal insulin receptor exacerbates intestinal inflammation by promoting tissue resident memory T cells differentiation through EZH2.

机构信息

Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.

Department of General Surgery, Army 953 Hospital, Shigatse Branch of Xinqiao Hospital, Army Medical University, Shigatse, 857000, China.

出版信息

J Transl Med. 2024 Jan 19;22(1):78. doi: 10.1186/s12967-023-04789-x.

DOI:10.1186/s12967-023-04789-x

PMID:38243324

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10797971/

Abstract

BACKGROUND

Inflammatory Bowel Diseases (IBD), an autoimmune disease characterised by abnormal intestinal immunity, are related to vital morbidity around the world. However, therapeutic agents for IBD have not achieved desired benefit. Exploring new therapeutic targets for IBD, especially based on its abnormally intestinal immunity, could alleviate the flare-up and worsening of IBD. Tissue resident memory T cells (TRM) are core of multiple autoimmune diseases, including IBD. However, the mechanism of TRM differentiation remains to be investigated.

METHODS

The alterations in mRNA and lncRNA profile of intestinal intraepithelial lymphocytes (IELs), the largest component of intestinal TRM, were analyzed in DSS-induced chronic colitis. Based on it, we examined the function of rectal insulin instillation in a dextran sodium sulfate (DSS) induced chronic colitis. Furthermore, we investigated the downstream-target of the insulin pathway-EZH2 and the crucial role of EZH2 in intestinal tissue resident memory T cell differentiation by utilizing EZH2CD4 mice.

RESULTS

Insulin receptor (INSR) expression was found to be significantly reduced. Activation of mucosal insulin pathway by rectal insulin instillation exacerbated colitis by disrupting IELs subgroups and up-regulating TNF-ɑ and IL-17 expression. Rectal insulin instillation promoted EZH2 expression and EZH2 inhibition alleviated chronic colitis. EZH2CD4 mice restored the normal IEL subgroups and suppressed TNF-ɑ and IL-17 expression, exhibiting alleviated colitis. IELs from EZH2CD4 mice exhibit significant changes in TRM related phenotype. CD4TRM was significantly increased in chronic colitis and decreased in EZH2CD4 mice.

CONCLUSION

Insulin receptor of intestinal mucosal T-cells could promote intestinal TRM differentiation via EZH2. Our discoveries suggest that therapies targeting colonic INSR and EZH2 could be potential treatment for IBD based on its regulatory effects on TRM. Insulin receptor inhibitors rather than insulin should be applied during colitis-active phase. In addition, EZH2 shows to be a downstream signal of the insulin pathway and EZH2 inhibitor could alleviating intestinal inflammation. However, the critical role of EZH2 in TRM differentiation restricts the anti-tumor effects of EZH2 inhibitor in vivo.

摘要

背景

炎症性肠病（IBD）是一种以肠道免疫异常为特征的自身免疫性疾病，在全球范围内与重要的发病率有关。然而，IBD 的治疗药物并未达到预期的疗效。探索 IBD 的新治疗靶点，特别是基于其异常的肠道免疫，可能会减轻 IBD 的发作和恶化。组织驻留记忆 T 细胞（TRM）是包括 IBD 在内的多种自身免疫性疾病的核心。然而，TRM 分化的机制仍有待研究。

方法

分析 DSS 诱导的慢性结肠炎中肠道上皮内淋巴细胞（IEL）的 mRNA 和 lncRNA 谱的变化，IEL 是肠道 TRM 的最大组成部分。在此基础上，我们研究了直肠胰岛素灌注在葡聚糖硫酸钠（DSS）诱导的慢性结肠炎中的作用。此外，我们利用 EZH2CD4 小鼠研究了胰岛素通路下游靶标 EZH2 以及 EZH2 在肠道组织驻留记忆 T 细胞分化中的关键作用。

结果

发现胰岛素受体（INSR）表达明显降低。通过直肠胰岛素灌注激活黏膜胰岛素通路，通过破坏 IEL 亚群和上调 TNF-ɑ 和 IL-17 表达，加重结肠炎。直肠胰岛素灌注促进 EZH2 表达，EZH2 抑制减轻慢性结肠炎。EZH2CD4 小鼠恢复正常 IEL 亚群，抑制 TNF-ɑ 和 IL-17 表达，缓解结肠炎。EZH2CD4 小鼠的 IEL 表现出明显的 TRM 相关表型变化。慢性结肠炎中 CD4TRM 明显增加，EZH2CD4 小鼠中减少。

结论

肠道黏膜 T 细胞的胰岛素受体可通过 EZH2 促进肠道 TRM 分化。我们的发现表明，针对结肠 INSR 和 EZH2 的治疗方法可能基于其对 TRM 的调节作用成为 IBD 的潜在治疗方法。在结肠炎活动期应应用胰岛素受体抑制剂而不是胰岛素。此外，EZH2 显示为胰岛素通路的下游信号，EZH2 抑制剂可缓解肠道炎症。然而，EZH2 在 TRM 分化中的关键作用限制了 EZH2 抑制剂在体内的抗肿瘤作用。