Activation of Liver X Receptor ? Sensitizes Mice to T-Cell Mediated Hepatitis.

ABSTRACT: Autoimmune hepatitis (AIH) is an inflammatory disease of the liver. Liver X receptors (LXRs), including the ? and ? isoforms, are previously known for their anti-inflammatory activities. The goal of this study is to determine whether and how LXR plays a role in AIH. LXR? gain-of-function and loss-of-function mouse models were used, in conjunction with the concanavalin A (ConA) model of T-cell mediated hepatitis. We first showed that the hepatic expression of LXR? was decreased in the ConA model of hepatitis and in human patients with AIH. In the ConA model, we were surprised to find that activation of LXR? in the constitutively activated VP-LXR? whole-body knock-in (LXR?-KI) mice exacerbated ConA-induced AIH, whereas the LXR?-/- mice showed attenuated ConA-induced AIH. Interestingly, hepatocyte-specific activation of LXR? in the fatty acid binding protein-VP-LXR? transgenic mice did not exacerbate ConA-induced hepatitis. Mechanistically, the sensitizing effect of the LXR?-KI allele was invariant natural killer T (iNKT)-cell dependent, because the sensitizing effect was abolished when the LXR?-KI allele was bred into the NKT-deficient CD1d-/- background. In addition, LXR?-enhanced ConA-induced hepatitis was dependent on interferon gamma. In contrast, adoptive transfer of hepatic iNKT cells isolated from LXR?-KI mice was sufficient to sensitize CD1d-/- mice to ConA-induced AIH. Conclusion: Activation of LXR? sensitizes mice to ConA-induced AIH in iNKT and interferon gamma-dependent manner. Our results suggest that LXR? plays an important role in the development of AIH.

SUBMITTER: Gao L 

PROVIDER: S-EPMC7603537 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature