Li Jian, Doty Andria, Glover Sarah C
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Florida P.O. Box 100214, Gainesville, FL, 32610 USA.
Inflamm Cell Signal. 2016;3(3). doi: 10.14800/ics.1404. Epub 2016 Aug 29.
Innate lymphoid cells (ILCs) are emerging as important components of our immune system that have critical effector and regulatory functions in both innate and adaptive immune responses. They are enriched at mucosal surfaces, such as lung and intestine. Our previous work has shown that LineageCRTH2CD45NKp44CD117CD127ILC1s accumulated in the inflamed terminal ileum of patients with Crohn's disease (CD) at the expense of NKp44ILC3s. This phenotype conversion impairs the intestinal barrier integrity and contributes to the dysregulated immune responses of CD patients. Our next step was to search for pathways to modulate this phenotype switch. The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor. Initial studies of AHR concentrated on its role in the detoxification of xenobiotics. However, recent research has focused on the immune system. Especially, AHR pathway is proven to be essential for the maintenance of intestinal ILC3s in mouse models. We examined whether AHR pathway participated in the human intestinal ILC phenotype change in the inflamed terminal ileum of CD patients. As anticipated, NKp44ILC3s, NKp44ILC3s and ILC1s had differential AHR expression. This AHR signaling mediated CD117 expression on the surface of ILC3s. The conversion from ILC3 to ILC1 was accompanied by the downregulation of AHR expression. We further observed that there was a disparity between AHR protein expression and mRNA expression in the inflamed terminal ileum tissues of CD patients compared to unaffected areas. These findings suggest that AHR pathway is also important for human intestinal ILC phenotype regulation and impaired AHR signaling in the inflamed gut of CD patients possibly contributes to the ILC3/ILC1 conversion.
固有淋巴细胞（ILC）正逐渐成为我们免疫系统的重要组成部分，在固有免疫和适应性免疫反应中发挥关键的效应和调节功能。它们在黏膜表面大量存在，如肺和肠道。我们之前的研究表明，谱系CRTH2CD45NKp44CD117CD127 ILC1在克罗恩病（CD）患者发炎的回肠末端积聚，而NKp44 ILC3s数量减少。这种表型转换损害了肠道屏障的完整性，并导致CD患者免疫反应失调。我们的下一步是寻找调节这种表型转换的途径。芳烃受体（AHR）是一种依赖配体的转录因子。最初对AHR的研究集中在其在外源生物解毒中的作用。然而，最近的研究聚焦于免疫系统。特别是，在小鼠模型中已证明AHR信号通路对于维持肠道ILC3至关重要。我们研究了AHR信号通路是否参与CD患者发炎回肠末端的人肠道ILC表型变化。正如预期的那样，NKp44 ILC3s、NKp44 ILC3s和ILC1s具有不同的AHR表达。这种AHR信号传导介导了ILC3表面CD117的表达。从ILC3到ILC1的转换伴随着AHR表达的下调。我们进一步观察到，与未受影响区域相比，CD患者发炎回肠末端组织中AHR蛋白表达与mRNA表达存在差异。这些发现表明，AHR信号通路对于人类肠道ILC表型调节也很重要，并且CD患者发炎肠道中受损的AHR信号可能促成了ILC3/ILC1的转换。
