Ifnar1 signaling breaks the hepatic urea cycle to regulate adaptive immunity
Author:
Lercher Alexander, Bhattacharya Anannya, Popa Alexandra M., Caldera Michael, Schlapansky Moritz F., Baazim Hatoon, Majek Peter, Brunner Julia S., Kosack Lindsay J., Vitko Dijana, Pinter Theresa, Gürtl Bettina, Reil Daniela, Kalinke Ulrich, Bennett Keiryn L., Menche Jörg, Cheng Paul N., Schabbauer Gernot, Trauner Michael, Klavins Kristaps, Bergthaler AndreasORCID
Abstract
AbstractInfections induce complex host responses linked to antiviral defense, inflammation and tissue damage and repair. These processes are increasingly understood to involve systemic metabolic reprogramming. We hypothesized that the liver as a central metabolic hub may orchestrate many of these changes during infection. Thus, we investigated the systemic interplay between inflammation and metabolism in a mouse model of chronic viral infection and hepatitis. Here we show that virus-induced type I interferon (IFN-I) modulates wide-spread metabolic alterations of the liver in a hepatocyte-intrinsic Ifnar1-dependent way. Specifically, IFN-I repressed the transcription of numerous genes with metabolic function including Otc and Ass1, which encode enzymes of the urea cycle. This led to decreased arginine and increased ornithine concentrations in the circulation, resulting in suppressed virus-specific CD8 T cell responses and ameliorated liver pathology. These findings establish IFN-I-induced modulation of hepatic metabolism and the urea cycle as an endogenous mechanism of immunoregulation.
Publisher
Cold Spring Harbor Laboratory
Reference66 articles.
1. Systemic Viral Infections and Collateral Damage in the Liver 2. Ah Mew, N. , Simpson, K.L. , Gropman, A.L. , Lanpher, B.C. , Chapman, K.A. , and Summar, M.L. (1993). Urea Cycle Disorders Overview. 3. Baazim, H. , Schweiger, M. , Moschinger, M. , Xu, H. , Scherer, T. , Popa, A. , Gallage, S. , Ali, S.A. , Khamina, K. , Kosack, L. , et al. (2019). CD8 T cells induce cachexia in chronic viral infection. Nat. Immunol. In Press. 4. The role of the liver in metabolic homeostasis: Implications for inborn errors of metabolism 5. Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage
|
|