Type I Interferon Signaling Disrupts the Hepatic Urea Cycle and Alters Systemic Metabolism to Suppress T Cell Function

Abstract

Graphical Abstract Highlights d Chronic viral infection causes long-term transcriptome and proteome changes in the liver d Hepatocyte-intrinsic type I interferon (IFN-I) signaling regulates hepatic metabolism d IFN-I signaling reprograms the urea cycle in hepatocytes and alters serum metabolites d Serum levels of arginine and ornithine modulate T cell responses and pathology

Systemic Immunometabolism: Challenges and Opportunities

“…This is reflected by a recent study highlighting the differences between metabolic reprogramming of in vitro -activated T cells compared to their infection-activated counterparts in vivo ( Ma et al., 2019 ). Metabolic parameters such as organ-specific pH, partial pressure of oxygen, nutrient gradients, and disease-dependent changes of the metabolic environment are not considered by standard cell culture conditions, but clearly influence T cell activation ( Buck et al., 2017 ; Geiger et al., 2016 ; Johnson et al., 2018 ; Lercher et al., 2019 ; Ma et al., 2017 ; Murray, 2016 ; Nakaya et al., 2014 ; Roy et al., 2020 ; Sinclair et al., 2013 ). Similarly, tumor-associated fibroblasts have a high affinity for glucose and deplete the tumor microenvironment from glucose, resulting in metabolic competition that impairs the function of infiltrating tumor-specific T cells ( Chang et al., 2015 ).…”

“…Similarly, tumor-associated fibroblasts have a high affinity for glucose and deplete the tumor microenvironment from glucose, resulting in metabolic competition that impairs the function of infiltrating tumor-specific T cells ( Chang et al., 2015 ). Next to glucose, numerous other extracellular metabolites, including amino acids, may modulate T cell function in the tumor microenvironment or during chronic viral infection ( Geiger et al., 2016 ; Lercher et al., 2019 ; Murray et al., 2015 ).…”

Hepatocyte-intrinsic type I interferon signaling reprograms metabolism and reveals a novel compensatory mechanism of the tryptophan-kynurenine pathway in viral hepatitis

“…IFN-I is an important antiviral cytokine and important for pathogen control during viral hepatitis [17,57]. IFN-I can also initiate metabolic reprogramming in immune cells and tissue-resident cells [11,[19][20][21]. Virus-induced IFN-I triggers an endogenous regulatory circuit in hepatocytes to ameliorate tissue damage in viral hepatitis via increased local degradation and systemic repression of amino acids and accumulation of downstream metabolites [11].…”

“…Hence, it has to integrate immune responses to pathogens and immunogenic tolerance to commensals [4][5][6]. Hepatocytes are major coordinators of these processes, as they are not only metabolically highly active cells, but also important signaling platforms for innate and adaptive immunity [7][8][9][10][11].…”

“…Further, IFN-I contributes to metabolic reprogramming not only in immune cells [19][20][21], but also fibroblasts [20] or epithelial cells [21]. In hepatocytes, virus-induced IFN-I signaling regulates redox homeostasis and orchestrates wide-spread reprogramming of central metabolic pathways in hepatocytes, including lipid and amino acid metabolism [11,22]. During viral hepatitis, this specifically reduces circulating amino acids, resulting in repression of antiviral T cell responses and ameliorated T cellmediated tissue damage [11].…”