Transferrin Is Up-Regulated by Microbes and Acts as a Negative Regulator of Immunity to Induce Intestinal Immunotolerance  

作　　者：Xiaopeng Tang Mingqian Fang Ruomei Cheng Junkun Niu Xiaoshan Huang Kuanhong Xu Gan Wang Yang Sun Zhiyi Liao Zhiye Zhang James Mwangi Qiumin Lu Aili Wang Longbao Lv Chao Liu Yinglei Miao Ren Lai 

机构地区：[1]Engineering Laboratory of Peptides of Chinese Academy of Sciences,Key Laboratory of Bioactive Peptides of Yunnan Province,KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases,National Resource Center for Non-Human Primates,National Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility),and Sino-African Joint Research Center,New Cornerstone Science Institute,Kunming Institute of Zoology,the Chinese Academy of Sciences,No.17 Longxin Road,Kunming,Yunnan,650201,China [2]School of Basic Medicine,Qingdao University,Qingdao 266071,Shandong,China. [3]Department of Gastroenterology,First Affiliated Hospital of Kunming Medical University,Yunnan Institute of Digestive Disease,Kunming 650032,Yunnan,China [4]Yunnan Province Clinical Research Center for Digestive Diseases,Kunming 650032,Yunnan,China [5]Kunming College of Life Science,University of Chinese Academy of Sciences,Kunming 650204,Yunnan,China [6]Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences,University of Science and Technology of China,Hefei 230027,Anhui,China [7]Center for Evolution and Conservation Biology,Southern Marine Science and Engineering Guangdong Laboratory,Guangzhou 511458,Guangdong,China.

出　　处：《Research》2024年第3期761-774,共14页研究（英文）

基　　金：the National Key Research and Development Program of China(2022YFF1301601);the Ministry of Science and Technology of China(2018YFA0801403 and 2022YFC2105003);the National Science Foundation of China(31930015,32100907,U2002219,and 32371162);the Chinese Academy of Sciences(KFJ-BRP-008 and SAJC202103);Yunnan Province(202003AD150008,202202AA100002 and 202301AS070074);the Kunming Science and Technology Bureau(2022SCP007);the New Cornerstone Investigator Program from Shenzhen New Cornerstone Science Foundation,Excellent Young Scientists Foundation of Shandong Province(ZR2023YQ025);the Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(TFJC2023010007);the PI Project of Southern Marine Science and Engineering Guangdong Laboratory(Guangzhou)(GML2021GD0807).

摘　　要：Cross-talks (e.g., host-driven iron withdrawal and microbial iron uptake between host gastrointestinal tract and commensal microbes) regulate immunotolerance and intestinal homeostasis. However, underlying mechanisms that regulate the cross-talks remain poorly understood. Here, we show that bacterial products up-regulate iron-transporter transferrin and transferrin acts as an immunosuppressor by interacting with cluster of differentiation 14 (CD14) to inhibit pattern recognition receptor (PRR) signaling and induce host immunotolerance. Decreased intestinal transferrin is found in germ-free mice and human patients with ulcerative colitis, which are characterized by impaired intestinal immunotolerance. Intestinal transferrin and host immunotolerance are returned to normal when germ-free mice get normal microbial commensalism, suggesting an association between microbial commensalism, transferrin, and host immunotolerance. Mouse colitis models show that transferrin shortage impairs host’s tolerogenic responses, while its supplementation promotes immunotolerance. Designed peptide blocking transferrin–CD14 interaction inhibits immunosuppressive effects of transferrin. In monkeys with idiopathic chronic diarrhea, transferrin shows comparable or even better therapeutic effects than hydrocortisone. Our findings reveal that by up-regulating host transferrin to silence PRR signaling, commensal bacteria counteract immune activation induced by themselves to shape host immunity and contribute for intestinal tolerance.

关 键 词：IMPAIRED IMMUNITY tolerance 

分 类 号：R574[医药卫生—消化系统]