膽汁酸代謝物調控TH17和Treg細胞的分化
作者：
小柯機器人發布時間：2019/11/28 15:29:51
美國哈佛醫學院Jun R. Huh、紐約大學醫學院Dan R. Littman和史丹福大學Michael A. Fischbach等研究人員合作發現，膽汁酸代謝物調控TH17和Treg細胞的分化。2019年11月27日，《自然》在線發表了這項成果。
研究人員表示，膽汁酸在哺乳動物的腸道中很豐富，在那裡它們經過細菌介導的轉化而生成大量的生物活性分子。儘管已知膽汁酸會影響宿主代謝、癌症進展和先天免疫，但尚不清楚它們是否會影響適應性免疫細胞，例如表達IL-17a的輔助性T細胞（TH17細胞）或調節性T細胞（Treg細胞）。
研究人員篩選了膽汁酸代謝物的庫，並鑑定了膽甾酸（LCA）的兩種不同衍生物，即3-oxoLCA和isoalloLCA，作為小鼠中的T細胞調節劑。3-OxoLCA通過直接結合關鍵類視黃醇相關孤兒受體γt（RORγt）抑制TH17細胞的分化，而isoalloLCA通過產生線粒體活性氧（mitoROS）來提高Treg細胞的分化，從而導致FOXP3的表達增加。isoalloLCA介導的Treg細胞分化增強需要Foxp3增強子，即保守的非編碼序列（CNS）3；這代表了一種不同於先前確定的增加Treg細胞分化代謝物（需要CNS1）的作用方式。在小鼠體內注射3-oxoLCA和isoalloLCA分別降低了腸道固有層TH17細胞分化以及提高了Treg細胞分化。這些數據表明膽汁酸代謝物通過直接調節TH17和Treg細胞的平衡來控制宿主免疫反應的機制。
附：英文原文
Title: Bile acid metabolites control T H 17 and T reg cell differentiation
Author: Saiyu Hang, Donggi Paik, Lina Yao, Eunha Kim, Trinath Jamma, Jingping Lu, Soyoung Ha, Brandon N. Nelson, Samantha P. Kelly, Lin Wu, Ye Zheng, Randy S. Longman, Fraydoon Rastinejad, A. Sloan Devlin, Michael R. Krout, Michael A. Fischbach, Dan R. Littman, Jun R. Huh
Issue&Volume: 2019-11-27
Abstract: Bile acids are abundant in the mammalian gut, where they undergo bacteria-mediated transformation to generate a large pool of bioactive molecules. Although bile acids are known to affect host metabolism, cancer progression and innate immunity, it is unknown whether they affect adaptive immune cells such as T helper cells that express IL-17a (TH17 cells) or regulatory T cells (Treg cells). Here we screen a library of bile acid metabolites and identify two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice. 3-OxoLCA inhibited the differentiation of TH17 cells by directly binding to the key transcription factor retinoid-related orphan receptor-t (RORt) and isoalloLCA increased the differentiation of Treg cells through the production of mitochondrial reactive oxygen species (mitoROS), which led to increased expression of FOXP3. The isoalloLCA-mediated enhancement of Treg cell differentiation required an intronic Foxp3 enhancer, the conserved noncoding sequence (CNS) 3; this represents a mode of action distinct from that of previously identified metabolites that increase Treg cell differentiation, which require CNS1. The administration of 3-oxoLCA and isoalloLCA to mice reduced TH17 cell differentiation and increased Treg cell differentiation, respectively, in the intestinal lamina propria. Our data suggest mechanisms through which bile acid metabolites control host immune responses, by directly modulating the balance of TH17 and Treg cells. Screening of a library of bile acid metabolites revealed two derivatives of lithocholic acid that act as regulators of T helper cells that express IL-17a and regulatory T cells, thus influencing host immune responses.
DOI: 10.1038/s41586-019-1785-z
Source: https://www.nature.com/articles/s41586-019-1785-z