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.
Highlights
The liver is an immunoprivileged site, autoimmune liver diseases, such as autoimmune hepatitis (AIH), develop globally in diverse ethnic groups [1]
Given that toll-like receptors (TLRs)-mediated inflammatory cytokine production is involved in the development of autoimmune liver diseases [12] and that TAM receptor tyrosine kinases (RTKs) are inhibitors of inflammatory responses [28], we examined the expression of inflammatory cytokines in the liver of TAM2/2 mice
Several attempts have been made to develop animal models that can reflect the persistent liver damage occurring in human AIH
Summary
The liver is an immunoprivileged site, autoimmune liver diseases, such as autoimmune hepatitis (AIH), develop globally in diverse ethnic groups [1]. AIH is a progressive inflammatory liver disorder that is characterized histologically by interface hepatitis and serologically by high levels of transaminases and the presence of non-organ specific autoantibodies. The etiology of the disease and the mechanisms leading to liver damage in AIH are poorly understood. One reason for this limited understanding regarding the etiology of AIH is the absence of reliable animal models. Several mouse models of AIH have been described [5,6,7,8] None of these models show persistent autoimmune liver damage [9]. Activation of toll-like receptors (TLRs) is engaged to break the immuno-tolerant status of the liver and convert autoreactivity into overt AIH [12]
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