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Differential and Overlapping Immune Programs Regulated by IRF3 and IRF5 in Plasmacytoid Dendritic Cells

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Differential and Overlapping Immune Programs Regulated by IRF3 and IRF5 in Plasmacytoid Dendritic Cells Differential and Overlapping Immune Programs Regulated by IRF3 and IRF5 in Plasmacytoid Dendritic Cells This information is current as Kwan T. Chow, Courtney Wilkins, Miwako Narita, Richard of September 28, 2021. Green, Megan Knoll, Yueh-Ming Loo and Michael Gale, Jr. J Immunol published online 8 October 2018 http://www.jimmunol.org/content/early/2018/10/05/jimmun ol.1800221 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2018/10/05/jimmunol.180022 Material 1.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published October 8, 2018, doi:10.4049/jimmunol.1800221 The Journal of Immunology Differential and Overlapping Immune Programs Regulated by IRF3 and IRF5 in Plasmacytoid Dendritic Cells Kwan T. Chow,*,† Courtney Wilkins,* Miwako Narita,‡ Richard Green,* Megan Knoll,* Yueh-Ming Loo,* and Michael Gale, Jr.* We examined the signaling pathways and cell type–specific responses of IFN regulatory factor (IRF) 5, an immune-regulatory transcription factor. We show that the protein kinases IKKa, IKKb, IKK«, and TANK-binding kinase 1 each confer IRF5 phosphorylation/dimerization, thus extending the family of IRF5 activator kinases. Among primary human immune cell subsets, we found that IRF5 is most abundant in plasmacytoid dendritic cells (pDCs). Flow cytometric cell imaging revealed that IRF5 is specifically activated by endosomal TLR signaling. Comparative analyses revealed that IRF3 is activated in pDCs uniquely through RIG-I–like receptor (RLR) signaling. Transcriptomic analyses of pDCs show that the partitioning of TLR7/IRF5 and RLR/IRF3 pathways confers differential gene expression and immune cytokine production in pDCs, linking IRF5 with immune Downloaded from regulatory and proinflammatory gene expression. Thus, TLR7/IRF5 and RLR–IRF3 partitioning serves to polarize pDC response outcome. Strategies to differentially engage IRF signaling pathways should be considered in the design of immunotherapeutic approaches to modulate or polarize the immune response for specific outcome. The Journal of Immunology, 2018, 201: 000–000. nterferon regulatory factors (IRFs) are transcription factors of these IRFs and translocation into the nucleus to induce gene that regulate the intricate gene networks essential for coor- expression (6). Stimulation of some TLRs also activates IRF3 and http://www.jimmunol.org/ I dinating an appropriate and effective immune response (1, 2). IRF7 to induce type I IFNs (7). In particular, IRF3 and IRF7 have been extensively studied and In contrast to IRF3 and IRF7, IRF5 regulation and function are shown to regulate the induction of type I IFNs and other cytokines less well characterized. Mouse studies revealed essential roles of in response to pattern recognition receptor (PRR) recognition of IRF5 in the production of IFN-b and proinflammatory mediators, pathogen-associated molecular patterns (PAMPs) during virus including IL-6, IL-12, and TNF-a (8–12). In humans, carriers of infection (3, 4). During RNA virus infection, viral PAMP RNA autoimmune risk haplotypes at the IRF5 locus exhibit elevated motifs are recognized by RIG-I–like receptors (RLRs), leading to levels of IFN-a (13–16), and dendritic cells (DCs) from these RLR signaling activation and interaction with the adaptor MAVS carriers produced elevated TNF-a and IL-12 upon TLR stimula- (5). MAVS recruits TANK-binding kinase 1 (TBK1), which tion (17, 18). In HEK293 cells overexpressing TLR7, the TLR7/8 by guest on September 28, 2021 phosphorylates IRF3 and IRF7, leading to the homodimerization agonist R848 induced activation of an IRF5 reporter, accompanied by the translocation of IRF5–GFP into the nucleus (19). TBK1 *Department of Immunology, Center for Innate Immunity and Immune Disease, was reported to phosphorylate IRF5 (19, 20), and a kinase-dead University of Washington, Seattle, WA 98109; †Department of Biomedical Sciences, mutant of TBK1 or the related IKKε inhibited the TLR7-dependent City University of Hong Kong, Kowloon, Hong Kong Special Administrative Region; activation of a Gal4–IRF5 reporter (19). These results suggest that and ‡Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Niigata Prefecture 950-2181, Japan TBK1 and IKKε activate both IRF5 and IRF3. Subsequent reports ORCIDs: 0000-0003-1012-0797 (K.T.C.); 0000-0003-2007-1183 (M.N.). identified IKKb as the activating kinase of IRF5 (21, 22). MAVS Received for publication February 15, 2018. Accepted for publication September 13, overexpression was also shown to induce IRF5 dimerization in 2018. HEK293T cells (21, 22), and RIG-I and IRF5 coexpression rescued This work was supported by the Croucher Foundation Postdoctoral Fellowship, a cytokine production defects in Irf3/5/7-deficient mouse cells (23), National Research Service Award F32 Postdoctoral Fellowship from the National suggesting that both TLR and RLR stimulation may activate IRF5. Institutes of Health (NIH) to K.T.C. (AI115935), and NIH Grants AI104002, AI100625, and AI083019. Of note is that these studies have typically relied on over- expression approaches often in epithelial cell lines to evaluate K.T.C. designed and performed experiments and wrote the manuscript; C.W. and R.G. performed bioinformatics analyses; Y.-M.L. and M.K. performed experiments; IRF5 functions. In human plasmacytoid DC (pDC) cell lines, and M.G. directed the research and edited the manuscript. RNA interference–mediated IRF5 knockdown experiments have The microarray data presented in this article have been submitted to the Gene established IRF5 as a crucial mediator type I IFN induction Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number (21, 24). However, the relevant regulatory pathways, endogenous GSE108526. steps of IRF5 activation, and IRF5 transcriptional signatures Address correspondence and reprint requests to Dr. Michael Gale, Jr. and Dr. Yueh- Ming Loo, Department of Immunology, University of Washington, Office E383, Box have not been defined nor directly compared with signaling from 358059, 750 Republican Street, Seattle, WA 981909-4766. E-mail addresses: other IRFs. [email protected] (M.G.) and [email protected] (Y.-M.L.) In this study, we evaluated the IRF5 activation process and The online version of this article contains supplemental material. defined the IRF5 transcriptome. Our study shows that each IKK Abbreviations used in this article: DC, dendritic cell; DE, differentially expressed; kinase can direct IRF5 phosphorylation for dimerization/activation GO, gene ontology; HAU, hemagglutination unit; HCV, hepatitis C virus; IRF, IFN regulatory factor; PAMP, pathogen-associated molecular pattern; pDC, plasmacytoid and that IRF5 is variably present in different primary immune cell DC; PRR, pattern recognition receptor; RLR, RIG-I–like receptor; RNA-seq, RNA subsets wherein it is highly abundant in pDCs. Using robust assays sequencing; SeV, Sendai virus; siRNA, small interfering RNA; SS, similarity score; to assess and compare endogenous IRF5 and IRF3 activation in TBK1, TANK-binding kinase 1; xRNA, X region of the HCV genome. pDCs, we show that IRF5 is activated upon endosomal TLR7/8 Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$37.50 stimulation, whereas RLR stimulation leads to IRF3 activation. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800221 2 PARTITIONED SIGNALING OF IRF5 AND IRF3 High throughput transcriptomic analyses reveal that triggering pDCs and anti-IRF3 (D83B9; Cell Signaling Technology). AF680- or AF790- through TLR7/IRF5 and RLR/IRF3 pathways leads to a response conjugated secondary Abs were purchased from Jackson ImmunoResearch. that induces specific gene expression profiles and the production of ImageStream imaging flow cytometry distinct sets of cytokines for differential immune activation. This unique partitioning of TLR7/IRF5 and RLR/IRF3 signaling serves to PBMCs or enriched pDCs were stained with the following cell surface markers: CD3-FITC (UCHT1; BD Biosciences), CD14-AF488 (M5E2; BD drive expanded proinflammatory, immune regulatory, and antiviral Biosciences), CD19-FITC (HIB19; BD Biosciences), CD56-AF488 (B159; actions of pDCs. BD Biosciences), CD11c-FITC, HLA-DR-PE (L243; BioLegend), BCDA2- PE (AC144; Miltenyi Biotec), and FITC-conjugated lineage mixture panel 1 (BD Biosciences). Cells were fixed and permeabilized using the Cytofix/ Materials and Methods Cytoperm kit (Becton Dickinson) and stained with IRF5-AF647 Ab Cells (EPR6094; Abcam) and DAPI (Life Technologies). Stained cells were 3 CAL-1 was gifted by Dr. T. Maeda (Nagasaki University). PMDC05 cells acquired on an ImageStreamX Mark II imaging flow cytometer at 60 were from M. Narita
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