Transferrin Is Up-Regulated by Microbes and Acts as a Negative Regulator of Immunity to Induce Intestinal Immunotolerance
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
Affiliations
Xiaopeng Tang
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.
Mingqian Fang
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.
Ruomei Cheng
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.
Junkun Niu
Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University,
Yunnan Institute of Digestive Disease, Kunming 650032, Yunnan, China.
Xiaoshan Huang
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.
Kuanhong Xu
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.
Gan Wang
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.
Yang Sun
Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University,
Yunnan Institute of Digestive Disease, Kunming 650032, Yunnan, China.
Zhiyi Liao
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.
Zhiye Zhang
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.
James Mwangi
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.
Qiumin Lu
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.
Aili Wang
Center for Evolution and Conservation Biology, Southern Marine Science and Engineering Guangdong Laboratory, Guangzhou 511458, Guangdong, China.
Longbao Lv
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.
Chao Liu
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.
Yinglei Miao
Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University,
Yunnan Institute of Digestive Disease, Kunming 650032, Yunnan, China.
Ren Lai
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.
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.
