Enterogenous bacterial glycolipids are required for the generation of natural killer T cells mediated liver injury.
Glycolipids are potent activator of natural killer T (NKT) cells. The relationship between NKT cells and intestinal bacterial glycolipids in liver disorders remained unclear. We found that, in sharp contrast to specific pathogen-free (SPF) mice, germ-free (GF) mice are resistant to Concanavalin A (ConA)-induced liver injury. ConA treatment failed to trigger the activation of hepatic NKT cells in GF mice. These defects correlated with the sharply reduced levels of CD1d-presented glycolipid antigens in ConA-treated GF mice compared with SPF counterparts. Nevertheless, CD1d expression was similar between these two kinds of mice. The absence of intestinal bacteria did not affect the incidence of αGalCer-induced liver injury in GF mice. Importantly, we found the intestinal bacteria contain glycolipids which can be presented by CD1d and recognized by NKT cells. Furthermore, supplement of killed intestinal bacteria was able to restore ConA-mediated NKT cell activation and liver injury in GF mice. Our results suggest that glycolipid antigens derived from intestinal commensal bacteria are important hepatic NKT cell agonist and these antigens are required for the activation of NKT cells during ConA-induced liver injury. These finding provide a mechanistic explanation for the capacity of intestinal microflora to control liver inflammation.
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
Yingfeng
Y
Wei
Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing, 400038, China.
Benhua
B
Zeng
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
Jianing
J
Chen
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
Guangying
G
Cui
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
Chong
C
Lu
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
Wei
W
Wu
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
Jiezuan
J
Yang
Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing, 400038, China.
Hong
H
Wei
Institute of Immunology and Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.|Innovation Center for Cell Biology, Hefei National Laboratory for Physical Sciences at Microscale, Hefei 230027, China.
Rufeng
R
Xue
Institute of Immunology and Key Laboratory of Innate Immunity and Chronic Disease of CAS, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.|Innovation Center for Cell Biology, Hefei National Laboratory for Physical Sciences at Microscale, Hefei 230027, China.
Li
L
Bai
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
Zhi
Z
Chen
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
Lanjuan
L
Li
Department of Immunology, Kitasato University School of Medicine, Sagamihar, 108-8641, Japan.
Kazuya
K
Iwabuchi
Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, 0600815, Japan.
Toshimitsu
T
Uede
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA.
Luc
L
Van Kaer
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
Hongyan
H
Diao
D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism; D001426:Bacterial Proteins / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology*; D003208:Concanavalin A / Q000009:adverse effects*; D004195:Disease Models, Animal; D000069196:Gastrointestinal Microbiome; D005856:Germ-Free Life; D006017:Glycolipids / Q000276:immunology*; D007422:Intestines / Q000382:microbiology; D051379:Mice; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms
D055610:Antigens, CD1d; D001426:Bacterial Proteins; C584692:CD1d antigen, mouse; D006017:Glycolipids; D003208:Concanavalin A