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The Role of Interferon- Regulated Genes in the Immune System

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The Role of Interferon- Regulated Genes in the Immune System From the Department of Medicine Karolinska Institutet, Stockholm, Sweden THE ROLE OF INTERFERON- REGULATED GENES IN THE IMMUNE SYSTEM Maria Sjöstrand Stockholm 2017 All previously published papers were reproduced with permission from the publisher. Illustrations created using images designed by freepic and flaticon. Published by Karolinska Institutet. Printed by E-PRINT AB © Maria Sjöstrand, 2017 ISBN 978-91-7676-573-9 The role of interferon-regulated genes in the immune system THESIS FOR DOCTORAL DEGREE (Ph.D.) AKADEMISK AVHANDLING som för avläggande av medicine doktorsexamen vid Karolinska Institutet offentligen försvaras i CMM Lecture Hall, L8:00, Karolinska Universitetssjukhuset, Solna Friday February 17th 2017, at 9.00 By Maria Sjöstrand Principal Supervisor: Opponent: Alexander Espinosa, Assistant Professor Timothy B. Niewold, Associate Professor Unit of Experimental Rheumatology Department of Rheumatology Department of Medicine Division of Immunology Karolinska Institutet Mayo Clinic Co-supervisor: Examination Board: Marie Wahren-Herlenius, Professor Mikael Karlsson, Professor Unit of Experimental Rheumatology Department of Microbiology, Tumor and Cell Biology Department of Medicine Karolinska institutet Karolinska Institutet Karin Loré, Professor Clinical Immunology and Allergy Unit Department of Medicine Karolinska Institutet Mattias Magnusson, Associate Professor Department of Clinical and Experimental Medicine Linköping University ABSTRACT Type I interferons (IFNs) are potent inducers of the first-line defense against pathogens. Their activity leads to the up- and downregulation of a large number of genes with various effects on the immune system, including direct effects on the pathogens. Due to the strong response evoked by IFN signaling, the IFN pathway is tightly regulated by IFN stimulated genes to avoid detrimental effects of long-term exposure. If the IFN signaling pathway is not regulated properly, or for other reasons constantly activated, it can lead to interferonopathies and autoimmune diseases such as systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS). Indeed, many therapeutics targeting the IFN pathway are currently in clinical trials. In contrast, type I IFNs are used to treat certain types of cancer, virus infections and multiple sclerosis. The complex role of type I IFN signaling in disease is not well understood and need further characterization for better therapeutic inventions. The aim of this thesis was to identify genes that are regulated by type I IFNs and investigate their role in the immune system. To do this, we quantified the expression of interferon-regulated genes in sorted immune cells from patients with primary SS, and from individuals treated with IFNb. Using global gene expression analysis on PBMCs as well as qPCR on sorted cells, we could identify several genes that were differentially regulated by type I IFNs in different immune cell populations. Among them were TRIM21 that was upregulated in T cells and B cells, BAFF that was upregulated in T cells, monocytes and neutrophils and miR-150-5p that was selectively downregulated in monocytes. The downregulated expression of miR-150-5p consequently led to an increased expression of its target c-Myb. In addition, monocytes from patients with SLE displayed an increase in c-Myb target genes. When investigating the regulation of BAFF and TRIM21, we found that both were regulated by members of the interferon regulatory factor (IRF) family. Specifically, both were upregulated by IRF1 and IRF2, and downregulated by IRF4 and IRF8. To further investigate the role of TRIM21 in the immune system, we generated Trim21-/- mice. These mice were prone to granulocyte infiltrations and developed symptoms of autoimmune disease after being triggered by metal ear tags. We found that TRIM21 negatively regulates the immune response by ubiquitinating IRFs, and that naïve Trim21-/- mice control the development of eosinophils in the bone marrow. LIST OF PUBLICATIONS I. Type I IFN reduces micro-RNA-150 levels in monocytes and activates a c-Myb transcriptional program Alina Johansson, Maria Sjöstrand, Petra Bergman, Mohsen Khademi, Magnus Andersson, Fredrik Piehl, Ruxandra Covacu, Maja Jagodic, Alexander Espinosa Manuscript II. The expression of BAFF is controlled by IRF transcription factors Maria Sjöstrand, Alina Johansson, Lara Aqrawi, Tomas Olsson, Marie Wahren- Herlenius and Alexander Espinosa J Immunol 2016; 196:91-96; doi: 10.4049/jimmunol.1501061 III. Expression of the immune regulator tripartite-motif 21 is controlled by IFN regulatory factors Maria Sjöstrand*, Aurélie Ambrosi*, Susanna Brauner, Jenna Sullivan, Stephen Malin, Vijay K. Kuchroo, Alexander Espinosa and Marie Wahren-Herlenius J Immunol 2013; 191:3753-3763; doi: 10.4049/jimmunol.1202341 IV. Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway Alexander Espinosa*, Valerie Dardalhon*, Susanna Brauner*, Aurélie Ambrosi, Rowan Higgs, Fransisco J. Quintana, Maria Sjöstrand, Maija-Leena Eloranta, Joan Ní Gabhann, Ola Winqvist, Birgitta Sundelin, Caroline A. Jefferies, Björn Rozell, Vijay K. Kuchroo and Marie Wahren-Herlenius J Exp Med 2009; 206:1661-1671; doi: 10.1084/jem.20090585 V. TRIM21 controls the maturation of eosinophils in the bone marrow Maria Sjöstrand, William Nyberg, Alina Johansson and Alexander Espinosa Manuscript *These authors contributed equally LIST OF ABBREVIATIONS BAFF B cell activating factor cDC Conventional dendritic cells CDN Cyclic dinucleotides DDX41 DEAD-box helicase DNA Deoxyribonucleic acid GAS Interferon g-activated site IFN Interferon IFNAR Interferon-a/b receptor IKKi IkB kinase i IRF Interferon-regulated factor IRG Interferon-regulated gene ISG Interferon-stimulated gene ISGF3 Interferon-stimulated gene factor 3 ISRE Interferon-stimulated response element JAK1 Janus kinase 1 LPS Lipopolysaccharide MAVS Mitochondrial antiviral-signaling protein MDA5 Melanoma differentiation-associated gene 5 MS Multiple sclerosis MyD88 Myeloid differentiation primary response gene 88 NFkB Nuclear factor-kB pDC Plasmacytoid dendritic cell pSS Primary Sjögren’s syndrome PRR Pattern recognition receptor RIG-I Retinoic acid-inducible gene I RNA Ribonucleic acid SLE Systemic lupus erythematosus STAT Signal transducer and activator of transcription STING Stimulator of interferon genes TBK1 TANK-binding kinase TLR Toll-like receptor TRIM Tripartite-motif TYK2 Tyrosine kinase 2 TABLE OF CONTENTS 1. INTRODUCTION ................................................................................................................. 1 1.1. Type I IFN signaling ........................................................................................................................................ 1 1.1.1. Classical signaling pathway ........................................................................................................................................ 1 1.1.2. Non-classical signaling pathways ............................................................................................................................. 2 1.1.2.1. The p38 MAPK pathway ...................................................................................................................................... 2 1.1.2.2. The PI3K pathway ................................................................................................................................................. 3 1.2. The production of type I IFNs ...................................................................................................................... 3 1.2.1. MDA5 and RIG-I ....................................................................................................................................................... 3 1.2.2. STING and cGAS ...................................................................................................................................................... 3 1.2.3. TLRs and pDCs .......................................................................................................................................................... 4 1.3. Interferon regulatory factors ........................................................................................................................... 5 1.4. Interferon-regulated genes .............................................................................................................................. 6 1.4.1. ISGs in viral defense .................................................................................................................................................. 6 1.4.2. ISGs and immune regulation .................................................................................................................................... 6 1.5. Type I IFNs in immune disorders and disease ............................................................................................ 7 1.5.1. Type I interferonopathies .......................................................................................................................................... 7 1.5.2. The pathological mechanism behind SLE and SS ................................................................................................. 8 1.6. Type I IFNs in therapy .................................................................................................................................... 9 1.6.1. Targeting the IFN pathway ......................................................................................................................................
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