DOCSLIB.ORG

Phosphorylation of Microglial IRF5 and IRF4 by IRAK4 Regulates Inflammatory Responses to Ischemia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Phosphorylation of Microglial IRF5 and IRF4 by IRAK4 Regulates Inflammatory Responses to Ischemia cells Article Phosphorylation of Microglial IRF5 and IRF4 by IRAK4 Regulates Inflammatory Responses to Ischemia Conelius Ngwa, Abdullah Al Mamun, Yan Xu, Romana Sharmeen and Fudong Liu * Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; [email protected] (C.N.); [email protected] (A.A.M.); [email protected] (Y.X.); [email protected] (R.S.) * Correspondence: [email protected]; Tel.: +1-713-500-7038; Fax: +1-713-500-0660 Abstract: Background: Interferon Regulatory Factor (IRF) 5 and 4 play a determinant role in regu- lating microglial pro- and anti-inflammatory responses to cerebral ischemia. How microglial IRF5 and IRF4 signaling are activated has been elusive. We hypothesized that interleukin-1 receptor associated kinase 4 (IRAK4) phosphorylates and activates IRF5 and IRF4 in ischemic microglia. We aimed to explore the upstream signals of the two IRFs, and to determine how the IRAK4-IRF signaling regulates the expression of inflammatory mediators, and impacts neuropathology. Meth- ods: Spontaneously Immortalized Murine (SIM)-A9 microglial cell line, primary microglia and neurons from C57BL/6 WT mice were cultured and exposed to oxygen-glucose deprivation (OGD), followed by stimulation with LPS or IL-4. An IRAK4 inhibitor (ND2158) was used to examine IRAK40s effects on the phosphorylation of IRF5/IRF4 and the impacts on neuronal morphology by co-immunoprecipitation (Co-IP)/Western blot, ELISA, and immunofluorescence assays. Results: We confirmed that IRAK4 formed a Myddosome with MyD88/IRF5/IRF4, and phosphorylated both IRFs, which subsequently translocated into the nucleus. Inhibition of IRAK4 phosphorylation quenched microglial pro-inflammatory response primarily, and increased neuronal viability and Citation: Ngwa, C.; Mamun, A.A.; neurite lengths after ischemia. Conclusions: IRAK4 signaling is critical for microglial inflammatory Xu, Y.; Sharmeen, R.; Liu, F. responses and a potential therapeutic target for neuroinflammatory diseases including cerebral Phosphorylation of Microglial IRF5 ischemia. and IRF4 by IRAK4 Regulates Inflammatory Responses to Ischemia. Keywords: inflammation; IRAK4; IRF5; IRF4; ischemia; microglia Cells 2021, 10, 276. https://doi.org/ 10.3390/cells10020276 Academic Editor: Yasu-Taka Azuma 1. Introduction Received: 11 December 2020 Immune responses are a fundamental pathophysiological procedure in cerebral is- Accepted: 27 January 2021 Published: 30 January 2021 chemia [1], and microglial activation plays a central role in initiating and perpetuating the inflammatory response [2]. After cerebral ischemia, microglia are activated producing Publisher’s Note: MDPI stays neutral and releasing a plethora of cytokines, chemokines, cytotoxic mediators and trophic fac- with regard to jurisdictional claims tors, which consequently mediate pro- and anti-inflammatory responses [3–7]. Microglia in published maps and institutional with the pro-inflammatory phenotype are associated with detrimental outcomes [8,9]. In affiliations. contrast, microglia of the anti-inflammatory phenotype promote tissue repair and confer neuroprotective effects [10–13]. Over-activation of microglia exacerbates cerebral ischemic injury [11,14,15]; therefore, it has high translational value to modulate microglial activation via inhibiting or skewing the pro-inflammatory to the anti-inflammatory phenotype [11,12]. Our previous in vivo studies using genetic manipulations in animals have found inter- Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. feron regulatory factor 5 (IRF5) and 4 (IRF4) play critical roles in mediating microglial pro- This article is an open access article and anti-inflammatory response respectively after stroke. However, through which path- distributed under the terms and way IRF5/IRF4 mediate the microglial response remains elusive. Systemic inflammation conditions of the Creative Commons studies on macrophage activation have suggested interleukin-1 receptor-associated kinase Attribution (CC BY) license (https:// 4 (IRAK-4) and adaptor protein MyD88 are crucial in phosphorylation of IRFs [14–20]. We creativecommons.org/licenses/by/ hypothesize that the IRAK4-IRF signaling phosphorylates the two IRFs in microglia, and 4.0/). facilitates IRFs’ translocation from the cytoplasm to the nucleus to regulate gene expression Cells 2021, 10, 276. https://doi.org/10.3390/cells10020276 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 16 tor-associated kinase 4 (IRAK-4) and adaptor protein MyD88 are crucial in phosphoryla- Cells 2021, 10, 276 tion of IRFs [14–20]. We hypothesize that the IRAK4-IRF signaling phosphorylates2 ofthe 16 two IRFs in microglia, and facilitates IRFs’ translocation from the cytoplasm to the nu- cleus to regulate gene expression of inflammatory mediators. In this study, we specifi- callyof inflammatory performed a mediators. series of in Invitro this assays study, in we microglia specifically culture performed exposed ato series oxygen of glucosein vitro deprivatioassays in microglian (OGD), culturean in vitro exposed ischemia to oxygen model, glucoseto elucidate deprivation the molecular (OGD), mechanis an in vitrom. Theischemia interaction model, toof elucidateIRF5/IRF4 the with molecular MyD88 mechanism. and IRAK4 The was interaction examined. of IRF5/IRF4 The effects with of IRAK4MyD88 inhibition and IRAK4 on was the examined. activation Theof the effects two ofIRFs IRAK4 and inhibitionthe impacts on on the ischemic activation neurons of the weretwo IRFs determined and the. impacts on ischemic neurons were determined. 2. Materials and Methods 2.1. Spontaneously Immortalized Murine Micro Microgliaglia Culture Spontaneously immortalized murine microglia, SIM-A9_CRL-3265SIM-A9_CRL-3265 (American(American Type Culture Collection, ATCC ATCC,, Manassas, VA VA,, USA USA)) cells were cultured as previously de- scribed [21] [21].. Briefly Briefly cells were cultured in DMEM/F DMEM/F-12-12 medium_DFL15 medium_DFL15 (Caisson (Caisson Labor- Labo- atories,ratories, Smithfield, Smithfield, UT UT,, USA USA)) containing containing 10% 10% FBS, 5% HS, andand 1%1% P/S.P/S. Next, cells werewere gently shaken and detached from the culture vessel with phosph phosphateate buffered saline (PBS) containing 1 mM EDTA, 1 mM EGTA and 1 mg/mL D-glucose. The detached cells were containing 1 mM EDTA, 1 mM EGTA and 1 mg/mL D-glucose. The detached cells were counted with a hemocytometer, and rested for at least 24 h in a Forma Steri-Cycle CO2 counted with a hemocytometer, and rested for at least 24◦ h in a Forma Steri-Cycle CO2 incubator (Thermo Scientific, Waltham, MA, USA) at 37 C, 95% humidity and 5% CO2, incubator (Thermo Scientific, Waltham, MA, USA) at 37 °C, 95% humidity and 5% CO2, before treatments. The cell line can yield more than 5 million cells after culture and was before treatments. The cell line can yield more than 5 million cells after culture and was used for western blotting experiments (Figures1–3). used for western blotting experiments (Figures 1–3). Figure 1. IRF5 and IRF4 bindFigure to 1. MyD88 IRF5 and or IRAK4.IRF4 bind (A to, MyD88B) SIM-A9 or IRAK4. cell homogenates (A, B) SIM-A9 were cell subjectedhomogenates to Co-IP were withsubjected to Co-IP with anti-IRAK4 antibody followed by immunoblotting for p-IRF5/p-IRF4, t-IRF5/t-IRF4, anti-IRAK4 antibody followed by immunoblotting for p-IRF5/p-IRF4, t-IRF5/t-IRF4, and MyD88. (C, D) WB optical and MyD88. (C, D) WB optical density quantification of the ratio of p-IRF5 over t-IRF5 (C) and density quantification of the ratio of p-IRF5 over t-IRF5 (C) and p-IRF4 over t-IRF4 (D). (E, F) SIM-A9 cell homogenates p-IRF4 over t-IRF4 (D). (E, F) SIM-A9 cell homogenates were subjected to Co-IP with anti-MyD88 were subjected to Co-IP withantibody anti-MyD88 to detect antibody p-IRF5/p to detect-IRF4p-IRF5/p-IRF4 and t-IRF5/t-IRF4. and ( t-IRF5/t-IRF4.G, H) WB optical (G ,densityH) WB quantification optical density of the quantification of the ratio of p-IRF5ratio of over p-IRF5 t-IRF5 over (G t)- andIRF5 p-IRF4 (G) and over p-IRF4 t-IRF4 over (H). t- IgGIRF4 controls H). IgG were controls from were the same from homogenates the same ho- of each treatment. n = 3 independentmogenates of experiments/per each treatment. n condition. = 3 independent IB, immunoblot; experiments/per p, phosphorylated; condition. IB, immunoblot; t, total; IgG, p, immunoglobulin negative control.phosphorylated; One-way ANOVA.t, total; IgG, immunoglobulin negative control. One-way ANOVA. Cells 2021, 10, 276 3 of 16 CellsCells 22021021,, 1010,, xx FORFOR PEERPEER REVIEWREVIEW 33 ofof 1616 Figure 2. IRAK4 phosphorylates IRF5/IRF4. (A) SIM-A9 cells were treated with 8 μM ND2158, Figure 2. IRAK4Figure phosphorylates 2. IRAK4 phosphorylates IRF5/IRF4. (A IRF5/IRF4.) SIM-A9 cells(A) SIM were-A9 treated cells were with treated 8 µM ND2158, with 8 μM chosen ND2158, by MTS gradient chosen by MTS gradient viability assay. (B) After treatments, cell homogenates were immunob- viability assay.chosen (B) After by MTS treatments, gradient cellviability homogenates assay. (B) wereAfter immunoblotted.treatments, cell homogenates ImageJ quantified were imm ratiosunob- of p-IRAK4/t- lotted.lotted. ImageJImageJ quantifiedquantified ratiosratios ofof pp--IRAK4/tIRAK4/t--IRAK4IRAK4 ((CC),), pp--IRF5/tIRF5/t--IRF5IRF5 ((DD)),, andand pp--IRF4/tIRF4/t--IRF4IRF4 ((EE)) IRAK4 (C), p-IRF5/t-IRF5 (D), and p-IRF4/t-IRF4 (E) in (B). Data were obtained from 3 independent experiments.
Load more

Recommended publications
  • Comprehensive Study of Nuclear Receptor DNA Binding Provides a Revised Framework for Understanding Receptor Specificity
    ARTICLE https://doi.org/10.1038/s41467-019-10264-3 OPEN Comprehensive study of nuclear receptor DNA binding provides a revised framework for understanding receptor specificity Ashley Penvose 1,2,4, Jessica L. Keenan 2,3,4, David Bray2,3, Vijendra Ramlall 1,2 & Trevor Siggers 1,2,3 The type II nuclear receptors (NRs) function as heterodimeric transcription factors with the retinoid X receptor (RXR) to regulate diverse biological processes in response to endogenous 1234567890():,; ligands and therapeutic drugs. DNA-binding specificity has been proposed as a primary mechanism for NR gene regulatory specificity. Here we use protein-binding microarrays (PBMs) to comprehensively analyze the DNA binding of 12 NR:RXRα dimers. We find more promiscuous NR-DNA binding than has been reported, challenging the view that NR binding specificity is defined by half-site spacing. We show that NRs bind DNA using two distinct modes, explaining widespread NR binding to half-sites in vivo. Finally, we show that the current models of NR specificity better reflect binding-site activity rather than binding-site affinity. Our rich dataset and revised NR binding models provide a framework for under- standing NR regulatory specificity and will facilitate more accurate analyses of genomic datasets. 1 Department of Biology, Boston University, Boston, MA 02215, USA. 2 Biological Design Center, Boston University, Boston, MA 02215, USA. 3 Bioinformatics Program, Boston University, Boston, MA 02215, USA. 4These authors contributed equally: Ashley Penvose, Jessica L. Keenan. Correspondence
    [Show full text]
  • IRF5 Gene Interferon Regulatory Factor 5
    IRF5 gene interferon regulatory factor 5 Normal Function The protein produced from the IRF5 gene, called interferon regulatory factor 5 (IRF5), acts as a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity of certain genes. When a virus is recognized in the cell, the IRF5 gene is turned on (activated), which leads to the production of IRF5 protein. The protein binds to specific regions of DNA that regulate the activity of genes that produce interferons and other cytokines. Cytokines are proteins that help fight infection by promoting inflammation and regulating the activity of immune system cells. In particular, interferons control the activity of genes that help block the replication of viruses, and they stimulate the activity of certain immune system cells known as natural killer cells. Health Conditions Related to Genetic Changes Systemic scleroderma Several normal variations in the IRF5 gene have been associated with an increased risk of developing systemic scleroderma, which is an autoimmune disorder characterized by the buildup of scar tissue (fibrosis) in the skin and internal organs. Although the IRF5 gene is known to stimulate the immune system in response to viruses, it is unknown how the gene variations contribute to the increased risk of systemic scleroderma. Researchers believe that a combination of genetic and environmental factors may play a role in development of the condition. Rheumatoid arthritis MedlinePlus Genetics provides information about Rheumatoid arthritis Systemic lupus erythematosus MedlinePlus Genetics provides information about Systemic lupus erythematosus Ulcerative colitis MedlinePlus Genetics provides information about Ulcerative colitis Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/) 1 Autoimmune disorders Studies have associated normal variations in the IRF5 gene with an increased risk of several autoimmune disorders.
    [Show full text]
  • Transcription Factor IRF4 Drives Dendritic Cells to Promote Th2 Differentiation
    ARTICLE Received 30 May 2013 | Accepted 21 Nov 2013 | Published 20 Dec 2013 DOI: 10.1038/ncomms3990 Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation Jesse W. Williams1, Melissa Y. Tjota2,3, Bryan S. Clay2, Bryan Vander Lugt4, Hozefa S. Bandukwala2, Cara L. Hrusch5, Donna C. Decker5, Kelly M. Blaine5, Bethany R. Fixsen5, Harinder Singh4, Roger Sciammas6 & Anne I. Sperling1,2,5 Atopic asthma is an inflammatory pulmonary disease associated with Th2 adaptive immune responses triggered by innocuous antigens. While dendritic cells (DCs) are known to shape the adaptive immune response, the mechanisms by which DCs promote Th2 differentiation remain elusive. Herein we demonstrate that Th2-promoting stimuli induce DC expression of IRF4. Mice with conditional deletion of Irf4 in DCs show a dramatic defect in Th2-type lung inflammation, yet retain the ability to elicit pulmonary Th1 antiviral responses. Using loss- and gain-of-function analysis, we demonstrate that Th2 differentiation is dependent on IRF4 expression in DCs. Finally, IRF4 directly targets and activates the Il-10 and Il-33 genes in DCs. Reconstitution with exogenous IL-10 and IL-33 recovers the ability of Irf4-deficient DCs to promote Th2 differentiation. These findings reveal a regulatory module in DCs by which IRF4 modulates IL-10 and IL-33 cytokine production to specifically promote Th2 differentiation and inflammation. 1 Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA. 2 Committee on Immunology, University of Chicago, 924 E. 57th Street, Chicago, Illinois 60637 USA. 3 Medical Scientist Training Program, University of Chicago, 924 E.
    [Show full text]
  • Epigenetic Services Citations
    Active Motif Epigenetic Services Publications The papers below contain data generated by Active Motif’s Epigenetic Services team. To learn more about our services, please give us a call or visit us at www.activemotif.com/services. Technique Target Journal Year Reference Justin C. Boucher et al. CD28 Costimulatory Domain- ATAC-Seq, Cancer Immunol. Targeted Mutations Enhance Chimeric Antigen Receptor — 2021 RNA-Seq Res. T-cell Function. Cancer Immunol. Res. doi: 10.1158/2326- 6066.CIR-20-0253. Satvik Mareedu et al. Sarcolipin haploinsufficiency Am. J. Physiol. prevents dystrophic cardiomyopathy in mdx mice. RNA-Seq — Heart Circ. 2021 Am J Physiol Heart Circ Physiol. doi: 10.1152/ Physiol. ajpheart.00601.2020. Gabi Schutzius et al. BET bromodomain inhibitors regulate Nature Chemical ChIP-Seq BRD4 2021 keratinocyte plasticity. Nat. Chem. Biol. doi: 10.1038/ Biology s41589-020-00716-z. Siyun Wang et al. cMET promotes metastasis and ChIP-qPCR FOXO3 J. Cell Physiol. 2021 epithelial-mesenchymal transition in colorectal carcinoma by repressing RKIP. J. Cell Physiol. doi: 10.1002/jcp.30142. Sonia Iyer et al. Genetically Defined Syngeneic Mouse Models of Ovarian Cancer as Tools for the Discovery of ATAC-Seq — Cancer Discovery 2021 Combination Immunotherapy. Cancer Discov. doi: doi: 10.1158/2159-8290 Vinod Krishna et al. Integration of the Transcriptome and Genome-Wide Landscape of BRD2 and BRD4 Binding BRD2, BRD4, RNA Motifs Identifies Key Superenhancer Genes and Reveals ChIP-Seq J. Immunol. 2021 Pol II the Mechanism of Bet Inhibitor Action in Rheumatoid Arthritis Synovial Fibroblasts. J. Immunol. doi: doi: 10.4049/ jimmunol.2000286. Daniel Haag et al.
    [Show full text]
  • PU.1 Cooperates with IRF4 and IRF8 to Suppress Pre-B-Cell Leukemia
    Leukemia (2016) 30, 1375–1387 © 2016 Macmillan Publishers Limited All rights reserved 0887-6924/16 www.nature.com/leu ORIGINAL ARTICLE PU.1 cooperates with IRF4 and IRF8 to suppress pre-B-cell leukemia SHM Pang1,2, M Minnich3, P Gangatirkar1,2, Z Zheng1, A Ebert3, G Song4, RA Dickins1,2,5, LM Corcoran1,2, CG Mullighan4, M Busslinger3, ND Huntington1,2, SL Nutt1,2 and S Carotta1,2,6 The Ets family transcription factor PU.1 and the interferon regulatory factor (IRF)4 and IRF8 regulate gene expression by binding to composite DNA sequences known as Ets/interferon consensus elements. Although all three factors are expressed from the onset of B-cell development, single deficiency of these factors in B-cell progenitors only mildly impacts on bone marrow B lymphopoiesis. Here we tested whether PU.1 cooperates with IRF factors in regulating early B-cell development. Lack of PU.1 and IRF4 resulted in a partial block in development the pre-B-cell stage. The combined deletion of PU.1 and IRF8 reduced recirculating B-cell numbers. Strikingly, all PU.1/IRF4 and ~ 50% of PU.1/IRF8 double deficient mice developed pre-B-cell acute lymphoblastic leukemia (B-ALL) associated with reduced expression of the established B-lineage tumor suppressor genes, Ikaros and Spi-B. These genes are directly regulated by PU.1/IRF4/IRF8, and restoration of Ikaros or Spi-B expression inhibited leukemic cell growth. In summary, we demonstrate that PU.1, IRF4 and IRF8 cooperate to regulate early B-cell development and to prevent pre-B-ALL formation.
    [Show full text]
  • Differential Expression of IFN Regulatory Factor 4 Gene in Human Monocyte-Derived Dendritic Cells and Macrophages
    Differential Expression of IFN Regulatory Factor 4 Gene in Human Monocyte-Derived Dendritic Cells and Macrophages This information is current as Anne Lehtonen, Ville Veckman, Tuomas Nikula, Riitta of September 27, 2021. Lahesmaa, Leena Kinnunen, Sampsa Matikainen and Ilkka Julkunen J Immunol 2005; 175:6570-6579; ; doi: 10.4049/jimmunol.175.10.6570 http://www.jimmunol.org/content/175/10/6570 Downloaded from References This article cites 79 articles, 45 of which you can access for free at: http://www.jimmunol.org/content/175/10/6570.full#ref-list-1 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 27, 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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Differential Expression of IFN Regulatory Factor 4 Gene in Human Monocyte-Derived Dendritic Cells and Macrophages1 Anne Lehtonen,2* Ville Veckman,* Tuomas Nikula,‡ Riitta Lahesmaa,‡ Leena Kinnunen,† Sampsa Matikainen,* and Ilkka Julkunen* In vitro human monocyte differentiation to macrophages or dendritic cells (DCs) is driven by GM-CSF or GM-CSF and IL-4, respectively.
    [Show full text]
  • 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.
    [Show full text]
  • View / Download
    Thynn HN, Chen XF, Dong SS, Guo Y, Yang TL. Commentary: An Allele-Specific Functional SNP Associated with Two Systemic Autoimmune Diseases Modulates IRF5 Expression by Long-Range Chromatin Loop Formation. J Immunological Sci. (2020); 4(1): 6-9 Journal of Immunological Sciences Commentary Article Open Access Commentary: An Allele-Specific Functional SNP Associated with Two Systemic Autoimmune Diseases Modulates IRF5 Expression by Long- Range Chromatin Loop Formation Hlaing Nwe Thynn, Xiao-Feng Chen, Shan-Shan Dong, Yan Guo, Tie-Lin Yang* Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical Informatics & Genomics Center, School of Life Science and Technol- ogy, Xi’an Jiaotong University, Xi’an, Shaanxi 710049, P. R. China Systemic Lupus Erythematosus (SLE) and Systemic Sclerosis Article Info Article Notes sharing similar pathogenic features. Genetic factors play important Received: February 14, 2020 (SSc) are two typical inflammatory systemic1 autoimmune diseases Accepted: March 20, 2020 roles in the pathogenesis of both diseases . We have witnessed huge success of genome-wide association studies (GWASs) in identifying *Correspondence: hundreds of susceptibility genetic variants associated with SLE Dr. Tie-Lin Yang, Ph.D., Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical and SSc, however, over 90% of which are located in noncoding Informatics & Genomics Center, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi into biological insights towards clinical applications. Currently, 710049, P. R. China; Telephone No: 86-29-82668463; Email: regions. It is challenging and important to translate GWAS findings [email protected]. compared with traditional genetic association studies, functional studies characterizing causal functional variants and downstream © 2020 Yang TL.
    [Show full text]
  • The Molecular Choreography of IRF4 and IRF8 with Immune System Partners
    The Molecular Choreography of IRF4 and IRF8 with Immune System Partners 1,2,4 1,3 1 HARINDER SINGH, ELKE GLASMACHER, ABRAHAM B. CHANG, 1 AND BRYAN VANDER LUGT 1Department of Discovery Immunology, Genentech Inc., South San Francisco, California 94080 4Correspondence: [email protected] The transcription factors IRF4 and IRF8 represent immune-specific members of the interferon regulatory family. They play major roles in controlling the development and functioning of innate and adaptive cells. Genes encoding these factors appear to have been coopted by the immune system via gene duplication and divergence of regulatory and protein coding sequences to enable the acquisition of unique molecular properties and functions. Unlike other members of the IRF family, IRF4 and IRF8 do not activate transcription of Type 1 interferon genes or positively regulate interferon-induced gene expression. Instead, they bind to unusual composite Ets-IRF or AP-1-IRF elements with specific Ets or AP-1 family transcription factors, respectively, and regulate the expression of diverse sets of immune response genes in innate as well as adaptive cells. The molecular cloning of interferon regulatory factor et al. 2012). Strikingly, this involves cooperative assembly 8 (IRF8) as interferon consensus sequence-binding pro- of IRF4 with AP-1 heterodimers containing a basic leucine tein (ICSBP) led to the realization that it bound inter- zipper transcription factor, AFT-like (BATF) subunit. feron response sequence elements (ISRE), albeit with This molecular property is shared by IRF8 but not by other low affinity, and antagonized ISRE-mediated gene acti- IRF family members, reminiscent of the molecular specif- vation (Driggers et al.
    [Show full text]
  • Deletion of Irf4 in T Cells Suppressed Autoimmune Uveitis and Dysregulated Transcriptional Programs Linked to CD4+ T Cell Differentiation and Metabolism
    International Journal of Molecular Sciences Article Deletion of Irf4 in T Cells Suppressed Autoimmune Uveitis and Dysregulated Transcriptional Programs Linked to CD4+ T Cell Differentiation and Metabolism Minkyung Kang 1,†, Hyun-Su Lee 1,†, Jin Kyeong Choi 1,2, Cheng-Rong Yu 1 and Charles E. Egwuagu 1,* 1 Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institute of Health, Bethesda, MD 20892, USA; [email protected] (M.K.); [email protected] (H.-S.L.); [email protected] (J.K.C.); [email protected] (C.-R.Y.) 2 Department of Immunology, Jeonbuk National University Medical School, Jeonju, Jeonbuk 54907, Korea * Correspondence: [email protected]; Tel.: +301-496-0049; Fax: +301-480-3914 † These authors contributed equally. Abstract: Interferon regulatory factor-4 (IRF4) and IRF8 regulate differentiation, growth and functions of lymphoid and myeloid cells. Targeted deletion of irf8 in T cells (CD4-IRF8KO) has been shown to exacerbate colitis and experimental autoimmune uveitis (EAU), a mouse model of human uveitis. We therefore generated mice lacking irf4 in T cells (CD4-IRF4KO) and investigated whether expression of IRF4 by T cells is also required for regulating T cells that suppress autoimmune diseases. Surprisingly, we found that CD4-IRF4KO mice are resistant to EAU. Suppression of EAU derived in part from inhibiting pathogenic responses of Th17 cells while inducing expansion of regulatory lymphocytes that secrete IL-10 and/or IL-35 in the eye and peripheral lymphoid tissues. Furthermore, CD4- IRF4KO T cells exhibit alterations in cell metabolism and are defective in the expression of two Citation: Kang, M.; Lee, H.-S.; Choi, Ikaros zinc-finger (IKZF) transcription factors (Ikaros, Aiolos) that are required for lymphocyte J.K.; Yu, C.-R.; Egwuagu, C.E.
    [Show full text]
  • Estrogen Receptor-Dependent Regulation of Dendritic Cell Development and Function
    REVIEW published: 10 February 2017 doi: 10.3389/fimmu.2017.00108 Estrogen Receptor-Dependent Regulation of Dendritic Cell Development and Function Sophie Laffont1*, Cyril Seillet2,3 and Jean-Charles Guéry1* 1 Centre de Physiopathologie de Toulouse Purpan (CPTP), Université de Toulouse, INSERM, CNRS, UPS, Toulouse, France, 2 Division of Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia, 3 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia Autoimmunity, infectious diseases and cancer affect women and men differently. Because they tend to develop more vigorous adaptive immune responses than men, women are less susceptible to some infectious diseases but also at higher risk of autoimmunity. The regulation of immune responses by sex-dependent factors probably involves several non-redundant mechanisms. A privileged area of study, however, concerns the role of sex steroid hormones in the biology of innate immune cells, especially dendritic cells (DCs). In recent years, our understanding of the lineage origin of DC populations has expanded, Edited by: and the lineage-committing transcription factors shaping peripheral DC subsets have Manfred B. Lutz, been identified. Both progenitor cells and mature DC subsets express estrogen receptors University of Würzburg, Germany (ERs), which are ligand-dependent transcription factors. This suggests that estrogens Reviewed by: may contribute to the reported sex differences in immunity by regulating DC biology. Meredith O’Keeffe, Monash University, Australia Here, we review the recent literature and highlight evidence that estrogen-dependent Pieter J. M. Leenen, activation of ERα regulates the development or the functional responses of particular DC Erasmus University Rotterdam, + Netherlands subsets.
    [Show full text]
  • Structural Basis of STAT2 Recognition by IRF9 Reveals Molecular Insights Into
    bioRxiv preprint doi: https://doi.org/10.1101/131714; this version posted April 28, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Structural basis of STAT2 recognition by IRF9 reveals molecular insights into 2 ISGF3 function 3 Srinivasan Rengachari1, Silvia Groiss1, Juliette, Devos1, Elise Caron2, Nathalie Grandvaux2,3, 4 Daniel Panne1* 5 1European Molecular Biology Laboratory, 38042 Grenoble, France 6 2 CRCHUM - Research center, Centre Hospitalier de l'Université de Montréal, Montréal, 7 H2X0A9, Québec, Canada 8 3 Department of Biochemistry and Molecular Medicine, Université de Montréal; Faculty of 9 Medicine, Université de Montréal, Montréal, H3C 3J7, Qc, Canada 10 *Corresponding author: email– [email protected], tel: +33–476207925 11 12 13 1 bioRxiv preprint doi: https://doi.org/10.1101/131714; this version posted April 28, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 14 15 Summary 16 Cytokine signalling is mediated by the activation of distinct sets of structurally homologous JAK 17 and STAT signalling molecules, which control nuclear gene expression and cell fate. A 18 significant expansion in the gene regulatory repertoire controlled by JAK/STAT signalling has 19 arisen by the selective interaction of STATs with IRF transcription factors.
    [Show full text]