TY - JOUR
T1 - Th2 signals induce epithelial injury in mice and are compatible with the biliary atresia phenotype
AU - Li, Jun
AU - Bessho, Kazuhiko
AU - Shivakumar, Pranavkumar
AU - Mourya, Reena
AU - Mohanty, Sujit Kumar
AU - Dos Santos, Jorge L.
AU - Miura, Irene K.
AU - Porta, Gilda
AU - Bezerra, Jorge A.
PY - 2011/11/1
Y1 - 2011/11/1
N2 - Biliary atresia (BA) is a destructive cholangiopathy of childhood in which Th1 immunity has been mechanistically linked to the bile duct inflammation and obstruction that culminate in liver injury. Based on reports of decreased Th1 cytokines in some patients and the development of BA in mice lacking CD4 + T cells, we hypothesized that Th1-independent mechanisms can also activate effector cells and induce BA. Here, we tested this hypothesis using Stat1 -/- mice, which lack the ability to mount Th1 immune responses. Infection of Stat1 -/-mice with rhesus rotavirus type A (RRV) on postnatal day 1 induced a prominent Th2 response, duct epithelial injury and obstruction within 7 days, and atresia shortly thereafter. A high degree of phosphorylation of the Th2 transcription factor Stat6 was observed; however, concurrent inactivation of Stat1 and Stat6 in mice did not prevent BA after RRV infection. In contrast, depletion of macrophages or combined loss of Il13 and Stat1 reduced tissue infiltration by lymphocytes and myeloid cells, maintained epithelial integrity, and prevented duct obstruction. In concordance with our mouse model, humans at the time of BA diagnosis exhibited differential hepatic expression of Th2 genes and serum Th2 cytokines. These findings demonstrate compatibility between Th2 commitment and the pathogenesis of BA, and suggest that patient subgrouping in future clinical trials should account for differences in Th2 status.
AB - Biliary atresia (BA) is a destructive cholangiopathy of childhood in which Th1 immunity has been mechanistically linked to the bile duct inflammation and obstruction that culminate in liver injury. Based on reports of decreased Th1 cytokines in some patients and the development of BA in mice lacking CD4 + T cells, we hypothesized that Th1-independent mechanisms can also activate effector cells and induce BA. Here, we tested this hypothesis using Stat1 -/- mice, which lack the ability to mount Th1 immune responses. Infection of Stat1 -/-mice with rhesus rotavirus type A (RRV) on postnatal day 1 induced a prominent Th2 response, duct epithelial injury and obstruction within 7 days, and atresia shortly thereafter. A high degree of phosphorylation of the Th2 transcription factor Stat6 was observed; however, concurrent inactivation of Stat1 and Stat6 in mice did not prevent BA after RRV infection. In contrast, depletion of macrophages or combined loss of Il13 and Stat1 reduced tissue infiltration by lymphocytes and myeloid cells, maintained epithelial integrity, and prevented duct obstruction. In concordance with our mouse model, humans at the time of BA diagnosis exhibited differential hepatic expression of Th2 genes and serum Th2 cytokines. These findings demonstrate compatibility between Th2 commitment and the pathogenesis of BA, and suggest that patient subgrouping in future clinical trials should account for differences in Th2 status.
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U2 - 10.1172/JCI57728
DO - 10.1172/JCI57728
M3 - Article
C2 - 22005305
AN - SCOPUS:80555142900
SN - 0021-9738
VL - 121
SP - 4244
EP - 4256
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -