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

Publikation

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

Wissenschaftlicher Artikel/Review - 26.11.2019

Lercher Alexander, Pikor Natalia, Reil Daniela, Ozsvár-Kozma Maria, Kalinke Ulrich, Ludewig Burkhard, Moriggl Richard, Bennett Keiryn L, Menche Jörg, Cheng Paul N, Schabbauer Gernot, Trauner Michael, Klavins Kristaps, Orlova Anna, Genger Jakob-Wendelin, Bhattacharya Anannya, Popa Alexandra M, Caldera Michael, Schlapansky Moritz F, Baazim Hatoon, Agerer Benedikt, Gürtl Bettina, Kosack Lindsay, Májek Peter, Brunner Julia S, Vitko Dijana, Pinter Theresa, Bergthaler Andreas

Zitation

Lercher A, Pikor N, Reil D, Ozsvár-Kozma M, Kalinke U, Ludewig B, Moriggl R, Bennett K, Menche J, Cheng P, Schabbauer G, Trauner M, Klavins K, Orlova A, Genger J, Bhattacharya A, Popa A, Caldera M, Schlapansky M, Baazim H, Agerer B, Gürtl B, Kosack L, Májek P, Brunner J, Vitko D, Pinter T, Bergthaler A. Type I Interferon Signaling Disrupts the Hepatic Urea Cycle and Alters Systemic Metabolism to Suppress T Cell Function. Immunity 2019; 51:1074-1087.e9.

Art

Wissenschaftlicher Artikel/Review (Englisch)

Zeitschrift

Immunity 2019; 51

Veröffentlichungsdatum

26.11.2019

eISSN (Online)

1097-4180

Seiten

1074-1087.e9

Kurzbeschreibung/Zielsetzung

Infections induce complex host responses linked to antiviral defense, inflammation, and tissue damage and repair. We hypothesized that the liver, as a central metabolic hub, may orchestrate systemic metabolic changes during infection. We infected mice with chronic lymphocytic choriomeningitis virus (LCMV), performed RNA sequencing and proteomics of liver tissue, and integrated these data with serum metabolomics at different infection phases. Widespread reprogramming of liver metabolism occurred early after infection, correlating with type I interferon (IFN-I) responses. Viral infection induced metabolic alterations of the liver that depended on the interferon alpha/beta receptor (IFNAR1). Hepatocyte-intrinsic IFNAR1 repressed the transcription of metabolic genes, including Otc and Ass1, which encode urea cycle enzymes. 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. VIDEO ABSTRACT.