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

被引：12

作者：

Lercher, Alexander ^{[1
]}

Popa, Alexandra M. ^{[1
]}

Viczenczova, Csilla ^{[1
]}

Kosack, Lindsay ^{[1
]}

Klavins, Kristaps ^{[1
]}

Agerer, Benedikt ^{[1
]}

Opitz, Christiane A. ^{[2
,3
,4
]}

Lanz, Tobias V. ^{[5
,6
]}

Platten, Michael ^{[6
,7
]}

Bergthaler, Andreas ^{[1
]}

机构：

[1] Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria

[2] German Canc Res Ctr, DKTK Brain Canc Metab Grp, Heidelberg, Germany

[3] Univ Hosp Heidelberg, Neurol Clin, Heidelberg, Germany

[4] Univ Hosp Heidelberg, Natl Ctr Tumor Dis, Heidelberg, Germany

[5] Stanford Univ, Dept Med, Sch Med, Div Rheumatol & Immunol, Stanford, CA 94305 USA

[6] Heidelberg Univ, Med Fac Mannheim, Dept Neurol, Mannheim, Germany

[7] German Canc Res Ctr, DKTK Clin Cooperat Unit Neuroimmunol & Brain Tumo, Heidelberg, Germany

来源：

PLOS PATHOGENS | 2020年 / 16卷 / 10期

基金：

欧洲研究理事会;

关键词：

LYMPHOCYTIC CHORIOMENINGITIS VIRUS; CYTOTOXIC T-CELLS; DENDRITIC CELLS; IMMUNE; LIVER; DISEASE; INNATE; IMMUNOMETABOLISM; INFLAMMATION; HOMEOSTASIS;

D O I：

10.1371/journal.ppat.1008973

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

The liver is a central regulator of metabolic homeostasis and serum metabolite levels. Hepatocytes are the functional units of the liver parenchyma and not only responsible for turnover of biomolecules but also act as central immune signaling platforms. Hepatotropic viruses infect liver tissue, resulting in inflammatory responses, tissue damage and hepatitis. Combining well-establishedin vitroandin vivomodel systems with transcriptomic analyses, we show that type I interferon signaling initiates a robust antiviral immune response in hepatocytes. Strikingly, we also identify IFN-I as both, sufficient and necessary, to induce wide-spread metabolic reprogramming in hepatocytes. IFN-I specifically rewired tryptophan metabolism and induced hepatic tryptophan oxidation to kynurenine viaTdo2, correlating with altered concentrations of serum metabolites upon viral infection. InfectedTdo2-deficient animals displayed elevated serum levels of tryptophan and, unexpectedly, also vast increases in the downstream immune-suppressive metabolite kynurenine. Thus,Tdo2-deficiency did not result in altered serum homeostasis of the tryptophan to kynurenine ratio during infection, which seemed to be independent of hepatocyte-intrinsic compensation via the IDO-axis. These data highlight that inflammation-induced reprogramming of systemic tryptophan metabolism is tightly regulated in viral hepatitis. Author summary Viral hepatitis is responsible for more than one million annual deaths worldwide and may progress to liver cirrhosis and hepatocellular carcinoma. The main metabolic cell type of the liver is the hepatocyte. In viral hepatitis, type I interferon (IFN-I) signaling rewires hepatocyte metabolism and serum metabolites to shape disease pathophysiology-an immune-regulatory circuit that might be therapeutically exploited. Here, we show that hepatocyte-intrinsic antiviral IFN-I signaling is both necessary and sufficient to induce wide-spread metabolic changes in hepatocytes. We identify an IFN-I-mediated induction of the hepatic kynurenine pathway via the rate-limiting and liver-specific enzyme TDO2, which controls serum homeostasis of tryptophan by converting it into kynurenine. Loss of TDO2 triggers a so far unknown compensatory mechanism, resulting in a vast increase of circulating kynurenine independent of hepatocyte intrinsic activity of the related IDO-enzymes. This study provides new insights into how inflammation reprograms metabolism of the liver and the kynurenine pathway during viral hepatitis.

引用

页数：22