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Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer.sup.1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver.sup.3, but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6.sup.+ CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6.sup.+ CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6.sup.+ CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity. Liver resident CD8 T cells have an essential role in immunopathology in a mouse model of nonalcoholic steatohepatitis, by becoming auto-aggressive following sequential transcriptional and metabolic activation steps ., Author(s): Michael Dudek [sup.1] , Dominik Pfister [sup.2] , Sainitin Donakonda [sup.1] [sup.3] , Pamela Filpe [sup.4] , Annika Schneider [sup.1] , Melanie Laschinger [sup.5] , Daniel Hartmann [sup.5] , [...]

Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness. Initial exposure to lipopolysaccharide (LPS) induces endotoxin tolerance, which reduces immunological reactions to LPS; here it is shown that primary LPS challenge is controlled by AhR, TDO2 and IL-10, whereas sustained effects require AhR, IDO1 and TGF-[beta], allowing for disease tolerance with reduced immunopathology in infections. Endotoxin tolerance link to tryptophan catabolism Endotoxin tolerance is an aspect of innate immunity in which prior exposure to a bacterial endotoxin (or lipopolysaccharide) reduces the host's response to subsequent exposure. Despite a recent resurgence of interest in this effect, the underlying mechanisms are poorly understood. This paper shows that the development of endotoxin tolerance is dependent on tryptophan catabolism through the sequential involvement of the metabolic enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2). This leads to kynurenine production which activates the aryl hydrocarbon receptor AhR. Primary endotoxin challenge is controlled by AhR, TDO2 and interleukin, whereas sustained tolerance requires AhR, IDO1 and the cytokine TGF-[beta], allowing for pathogen clearance with little immunopathology., Author(s): Alban Bessede [sup.1] [sup.2] , Marco Gargaro [sup.1] , Maria T. Pallotta [sup.1] , Davide Matino [sup.1] , Giuseppe Servillo [sup.1] , Cinzia Brunacci [sup.1] , Silvio Bicciato [sup.3] [...]

Abstract Immunoparalysis, characterised by impairments in neutrophil and monocyte/macrophage function, is common in critically ill patients. The theoretical ability of granulocyte colony-stimulating factor (G-CSF) to improve the functions of both [...]