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Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome.

ABSTRACT: Obesity-related insulin resistance is driven by low-grade chronic inflammation of metabolic tissues. In the liver, non-alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance and systemic glucose dysregulation. However, the immunological factors supporting these processes are poorly understood. We found that the liver accumulates pathogenic CD8+ T cell subsets which control hepatic insulin sensitivity and gluconeogenesis during diet-induced obesity in mice. In a cohort of human patients, CD8+ T cells represent a dominant intrahepatic immune cell population which links to glucose dysregulation. Accumulation and activation of these cells are largely supported by type I interferon (IFN-I) responses in the liver. Livers from obese mice upregulate critical interferon regulatory factors (IRFs), interferon stimulatory genes (ISGs), and IFN? protein, while IFN?R1-/- mice, or CD8-specific IFN?R1-/- chimeric mice are protected from disease. IFN?R1 inhibitors improve metabolic parameters in mice, while CD8+ T cells and IFN-I responses correlate with NAFLD activity in human patients. Thus, IFN-I responses represent a central immunological axis that governs intrahepatic T cell pathogenicity during metabolic disease.

SUBMITTER: Ghazarian M

PROVIDER: S-EPMC5447456 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome.

Ghazarian Magar M Revelo Xavier S XS Nøhr Mark K MK Luck Helen H Zeng Kejing K Lei Helena H Tsai Sue S Schroer Stephanie A SA Park Yoo Jin YJ Chng Melissa Hui Yen MHY Shen Lei L D'Angelo June Ann JA Horton Peter P Chapman William C WC Brockmeier Diane D Woo Minna M Engleman Edgar G EG Adeyi Oyedele O Hirano Naoto N Jin Tianru T Gehring Adam J AJ Winer Shawn S Winer Daniel A DA

Science immunology 20170401 10

Obesity-related insulin resistance is driven by low-grade chronic inflammation of metabolic tissues. In the liver, non-alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance and systemic glucose dysregulation. However, the immunological factors supporting these processes are poorly understood. We found that the liver accumulates pathogenic CD8+ T cell subsets which control hepatic insulin sensitivity and gluconeogenesis during diet-induced obesity in mice. In a cohor ...[more]

PMID: 28567448

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Project description:BACKGROUND:Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency caused by mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in hematopoietic cells. A high proportion of patients experience autoimmunity caused by a breakdown in T- and B-cell tolerance. Moreover, excessive production of type I interferon (IFN-I) by plasmacytoid dendritic cells (pDCs) contributes to autoimmune signs; however, the factors that trigger excessive innate activation have not been defined. OBJECTIVE:Neutrophil extracellular traps (NETs) emerged as major initiating factors in patients with diseases such as systemic lupus erythematosus and rheumatoid arthritis. In this study we explored the possible involvement of aberrant neutrophil functions in patients with WAS. METHODS:We evaluated the expression of a set of granulocyte genes associated with NETs in a cohort of patients with WAS and the presence of NET inducers in sera. Using a mouse model of WAS, we analyzed NET release by WASp-null neutrophils and evaluated the composition and homeostasis of neutrophils in vivo. By using depletion experiments, we assessed the effect of neutrophils in promoting inflammation and reactivity against autoantigens. RESULTS:Transcripts of genes encoding neutrophil enzymes and antimicrobial peptides were increased in granulocytes of patients with WAS, and serum-soluble factors triggered NET release. WASp-null neutrophils showed increased spontaneous NETosis, induced IFN-I production by pDCs, and activated B cells through B-cell activating factor. Consistently, their depletion abolished constitutive pDC activation, normalized circulating IFN-I levels, and, importantly, abolished production of autoantibodies directed against double-stranded DNA, nucleosomes, and myeloperoxidase. CONCLUSIONS:These findings reveal that neutrophils are involved in the pathogenic loop that causes excessive activation of innate cells and autoreactive B cells, thus identifying novel mechanisms that contribute to the autoimmunity of WAS.

Project description:BACKGROUND:Interferon ? (IFN?) is a cytokine whose production is increased endogenously in response to viral infection and in autoimmune diseases such as systemic lupus erythematosus (SLE). An elevated IFN? signature has been associated with clinically observed neuro-behavioural deficits such as mild cognitive impairment, fatigue, depression and psychosis in these diseases. However, the mechanisms underlying these neuropsychiatric symptoms remain largely unknown, and it is as yet unclear how IFN? signalling might influence central nervous system (CNS) function. Aberrant microglia-mediated synaptic pruning and function has recently been implicated in several neurodegenerative and neuropsychiatric diseases, but whether and how IFN? modulates these functions are not well defined. METHODS:Using a model of peripheral IFN? administration, we investigated gene expression changes due to IFNAR signalling in microglia. Bulk RNA sequencing on sorted microglia from wild type and microglia-specific Ifnar1 conditional knockout mice was performed to evaluate IFN? and IFNAR signalling-dependent changes in gene expression. Furthermore, the effects of IFN? on microglia morphology and synapse engulfment were assessed, via immunohistochemistry and flow cytometry. RESULTS:We found that IFN? exposure through the periphery induces a unique gene signature in microglia that includes the expected upregulation of multiple interferon-stimulated genes (ISGs), as well as the complement component C4b. We additionally characterized several IFN?-dependent changes in microglial phenotype, including expression of CD45 and CD68, cellular morphology and presynaptic engulfment, that reveal subtle brain region-specific differences. Finally, by specifically knocking down expression of IFNAR1 on microglia, we show that these changes are largely attributable to direct IFNAR signalling on microglia and not from indirect signalling effects through other CNS parenchymal cell types which are capable of IFN?-IFNAR signal transduction. CONCLUSIONS:Peripheral IFN? induces unique genetic and phenotypic changes in microglia that are largely dependent on direct signalling through microglial IFNAR. The IFN?-induced upregulation of C4b could play important roles in the context of aberrant synaptic pruning in neuropsychiatric disease.

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Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome.

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Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome.

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