Chen Feidi, Cao Anthony, Yao Suxia, Evans-Marin Heather L, Liu Han, Wu Wei, Carlsen Eric D, Dann Sara M, Soong Lynn, Sun Jiaren, Zhao Qihong, Cong Yingzi
Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555;
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555;
J Immunol. 2016 May 15;196(10):4390-9. doi: 10.4049/jimmunol.1501541. Epub 2016 Apr 11.
It has been shown recently that neutrophils are able to produce IL-22 and IL-17, which differentially regulate the pathogenesis of inflammatory bowel disease. However, it is still largely unknown how the neutrophil production of IL-22 and IL-17 is regulated, and their role in the pathogenesis of inflammatory bowel disease. In this study, we found that IL-23 promoted neutrophil production of IL-17 and IL-22. IL-23 stimulated the neutrophil expression of IL-23R as well as rorc and ahr. Retinoid acid receptor-related orphan receptor γ t and aryl-hydrocarbon receptor differentially regulated IL-23 induction of neutrophil IL-17 and IL-22. In addition, IL-23 induced the activation of mTOR in neutrophils. Blockade of the mTOR pathway inhibited IL-23-induced expression of rorc and ahr, as well as IL-17 and IL-22 production. By using a microbiota Ag-specific T cell-mediated colitis model, we demonstrated that depletion of neutrophils, as well as blockade of IL-22, resulted in a significant increase in the severity of colitis, thereby indicating a protective role of neutrophils and IL-22 in chronic colitis. Collectively, our data revealed that neutrophils negatively regulate microbiota Ag-specific T cell induction of colitis, and IL-23 induces neutrophil production of IL-22 and IL-17 through induction of rorc and ahr, which is mediated by the mTOR pathway.
最近研究表明，中性粒细胞能够产生IL-22和IL-17，它们对炎症性肠病的发病机制具有不同的调节作用。然而，中性粒细胞产生IL-22和IL-17的调节机制及其在炎症性肠病发病机制中的作用仍不清楚。在本研究中，我们发现IL-23可促进中性粒细胞产生IL-17和IL-22。IL-23刺激中性粒细胞表达IL-23R以及rorc和ahr。视黄酸受体相关孤儿受体γt和芳烃受体对中性粒细胞IL-17和IL-22的IL-23诱导具有不同的调节作用。此外，IL-23可诱导中性粒细胞中mTOR的激活。阻断mTOR通路可抑制IL-23诱导的rorc和ahr表达以及IL-17和IL-22的产生。通过使用微生物群抗原特异性T细胞介导的结肠炎模型，我们证明中性粒细胞的耗竭以及IL-22的阻断均导致结肠炎严重程度显著增加，从而表明中性粒细胞和IL-22在慢性结肠炎中具有保护作用。总的来说，我们的数据表明中性粒细胞对微生物群抗原特异性T细胞诱导的结肠炎具有负调节作用，并且IL-23通过诱导rorc和ahr来诱导中性粒细胞产生IL-22和IL-17，这一过程由mTOR通路介导。
