Dendritic Cells Regulate Treg-Th17 Axis in Obstructive Phase of Bile Duct Injury in Murine Biliary Atresia.
Several cell types are considered to be effector cells in bile duct injury in rhesus rotavirus (RRV)-induced experimental biliary atresia (BA). Here, we identified an increased T helper 17 (Th17) cell population in a BA mode. By depleting the Th17 cells, the BA symptoms (onset of jaundice, acholic stools and retarded growth) were attenuated and the survival rate was improved. Furthermore, we found that in mice with BA, the percentage of CD4+CD25highFoxp3+ T regulatory (Treg) cells decreased along with the increased percentage of Th17 cells. However, the absolute numbers of Treg and Th17 cells were both increased in liver of RRV-injected mice compared to saline-injected mice. The proportion of Th17 cells at 7 days post-infection was decreased if Treg cells isolated from normal adult mice, but not Treg cells from the livers of mice with BA, were intraperitoneally transferred on day 5 of life. In vitro experiments also showed that Treg cells from mice with BA had a diminished suppressive effect on Th17 cell generation. To determine the mechanisms, we investigated the production of cytokines in the liver. The level of IL-6, which has been shown to be abundantly secreted by activated dendritic cells (DCs), was remarkably elevated. Importantly, in a Treg/Th17 cell suppression assay, IL-6 was demonstrated to paralyze the Treg cells' suppressive effect on Th17 cells and eventually the unrestrained increase of Th17 cells contributed to bile duct injury. In conclusion, the DC-regulated Treg-Th17 axis, probably in conjunction with other effector T cells, aggravates progressive inflammatory injury at the time of ductal obstruction.
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yong-Jun
YJ
Liu
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Kang
K
Li
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Li
L
Yang
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Shao-Tao
ST
Tang
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xin-Xing
XX
Wang
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Guo-Qing
GQ
Cao
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Shuai
S
Li
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hai-Yan
HY
Lei
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xi
X
Zhang
D000818:Animals; D001652:Bile Ducts / Q000276:immunology / Q000503:physiopathology; D001656:Biliary Atresia / Q000276:immunology / Q000503:physiopathology*; D015153:Blotting, Western; D001651:Cholestasis, Extrahepatic / Q000276:immunology / Q000503:physiopathology; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000502:physiology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015870:Gene Expression; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D058504:Th17 Cells / Q000502:physiology*
D016207:Cytokines