Development of a spontaneous liver disease resembling autoimmune hepatitis in mice lacking tyro3, axl and mer receptor tyrosine kinases.

Abstract

Autoimmune hepatitis (AIH) is a severe type of chronic liver disease. The lack of appropriate animal models has resulted in a limited understanding regarding the etiology of AIH. Here, we demonstrated that mice deficient in Tyro3, Axl and Mer (TAM) receptor tyrosine kinases (RTKs) developed persistent inflammatory liver damage resembling AIH. Tyro3(-/-)Axl(-/-)Mer(-/-) triple mutant (TAM(-/-)) mice exhibited chronic hepatitis, manifested by progressive appearance of interface hepatitis, immune cell infiltrations and elevated inflammatory cytokine levels in the liver. Accordingly, increased levels of transaminases were observed. Moreover, characteristic autoantibodies and high levels of plasma immunoglobulin G for AIH were detected as TAM(-/-) mice aged. Finally, we provided evidence that the liver damage in TAM(-/-) mice mainly result from bone marrow-derived cells and could be rescued by transplantation of WT bone marrow cells. Results suggest that TAM RTKs play an important role in maintaining immune tolerance of the liver.