DOCSLIB.ORG

The AP-1 Transcription Factor C-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The AP-1 Transcription Factor C-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages This information is current as of September 28, 2021. Nicole Hannemann, Jutta Jordan, Sushmita Paul, Stephen Reid, Hanns-Wolf Baenkler, Sophia Sonnewald, Tobias Bäuerle, Julio Vera, Georg Schett and Aline Bozec J Immunol published online 15 March 2017 http://www.jimmunol.org/content/early/2017/03/15/jimmun Downloaded from ol.1601330 Supplementary http://www.jimmunol.org/content/suppl/2017/03/15/jimmunol.160133 http://www.jimmunol.org/ Material 0.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *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 © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 15, 2017, doi:10.4049/jimmunol.1601330 The Journal of Immunology The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages Nicole Hannemann,* Jutta Jordan,† Sushmita Paul,‡ Stephen Reid,x Hanns-Wolf Baenkler,* Sophia Sonnewald,x Tobias Ba¨uerle,† Julio Vera,‡ Georg Schett,* and Aline Bozec* Activation of proinflammatory macrophages is associated with the inflammatory state of rheumatoid arthritis. Their polarization and activation are controlled by transcription factors such as NF-kB and the AP-1 transcription factor member c-Fos. Surprisingly, little is known about the role of the AP-1 transcription factor c-Jun in macrophage activation. In this study, we show that mRNA and protein levels of c-Jun are increased in macrophages following pro- or anti-inflammatory stimulations. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment cluster analyses of microarray data using wild-type and c-Jun– Downloaded from deleted macrophages highlight the central function of c-Jun in macrophages, in particular for immune responses, IL production, and hypoxia pathways. Mice deficient for c-Jun in macrophages show an amelioration of inflammation and bone destruction in the serum-induced arthritis model. In vivo and in vitro gene profiling, together with chromatin immunoprecipitation analysis of macrophages, revealed direct activation of the proinflammatory factor cyclooxygenase-2 and indirect inhibition of the anti- inflammatory factor arginase-1 by c-Jun. Thus, c-Jun regulates the activation state of macrophages and promotes arthritis via differentially regulating cyclooxygenase-2 and arginase-1 levels. The Journal of Immunology, 2017, 198: 000–000. http://www.jimmunol.org/ he transcription factor family AP-1 is composed of homo- Whereas resident macrophages regulate tissue homeostasis, and heterodimeric complexes, which consist of Jun, Fos, macrophages recruited from the bloodstream activate specific T activating transcription factor, and musculoaponeurotic transcriptional programs, which allow them to polarize into pro- or fibrosarcoma proteins. These dimers are involved in different anti-inflammatory macrophages (4). AP-1 transcription factors cellular processes, such as proliferation, apoptosis, and differen- have been described to orchestrate inflammatory responses in tiation (1). In macrophages, AP-1 proteins can regulate inflam- macrophages, in particular by the expression of inflammatory matory processes through activation of cytokine production. For mediators (5). JunD for instance was recently shown to induce instance, the activation of IL and TLR leads to the initiation of an macrophage activation and cytokine secretion, by modulating their by guest on September 28, 2021 MAPK signaling cascade through MyD88, resulting in the acti- gene expression levels (6, 7). Furthermore, activation of JNK in vation of AP-1 in macrophages (2, 3). macrophages is required for the establishment of obesity-induced Macrophages perform diverse homeostatic functions in the de- insulin resistance and inflammation. JNK-deficient macrophages velopment, tissue repair, and immune responses against pathogens. expressed fewer proinflammatory chemokines and cytokines, such as Ccl2, Ccl5, IL-6, IL-12, and TNF (8). Additionally, JNK *Department of Internal Medicine 3—Rheumatology and Immunology, University blockade suppresses matrix metalloproteinases and thus inhibits ar- Hospital Erlangen, Friedrich Alexander University Erlangen–Nuremberg, 91054 thritic joint destruction in a rat adjuvant-induced arthritis model (9). Erlangen, Germany; †Preclinical Imaging Platform Erlangen, Institute of Radiology, University Hospital Erlangen, 91054 Erlangen, Germany; ‡Laboratory of Systems One JNK target is c-Jun, suggesting that c-Jun could also represent a Tumor Immunology, Department of Dermatology, University Hospital Erlangen, potent regulator of macrophage activation during inflammation. 91054 Erlangen, Germany; and xDivision of Biochemistry, Friedrich Alexander Uni- versity Erlangen–Nuremberg, 91054 Erlangen, Germany About 1% of the population worldwide is afflicted by rheumatoid arthritis, a chronic inflammatory disease of the joints, which is ORCIDs: 0000-0002-9185-6255 (S.S.); 0000-0002-3076-5122 (J.V.); 0000-0001- 8174-2118 (A.B.). characterized by synovial hyperplasia, cartilage degradation, and Received for publication August 2, 2016. Accepted for publication February 17, bone destruction (10). Macrophages are centrally involved in the 2017. process of arthritis (11). Their numbers in the synovial membrane This work was supported by funding from the Staedtler Foundation, Deutsche are increased during arthritis and exhibit a highly activated phe- Forschungsgemeinschaft Grants A01-CRC1181, Z-CRC1181, SPP1468 (IMMUNO- BONE program), and BO3811/1-1 (Emmy Noether program), and by Interdis- notype with increased expression of proinflammatory cytokines ziplina¨re Zentrum fur€ Klinische Forschung Project D23. (12). In addition to their proinflammatory properties, they contrib- The sequences presented in this article have been deposited in the National Center for ute to the destruction of bone and cartilage in the acute and chronic Biotechnology Information’s Gene Expression Omnibus database (https://www.ncbi. phases of arthritis (12). However, whether AP-1 proteins in mac- nlm.nih.gov/geo) under accession number GSE88898. rophages influence inflammatory arthritis still remains unknown. Address correspondence and reprint requests to Dr. Aline Bozec, Department of Internal Medicine 3—Rheumatology and Immunology, University Hospital Erlangen, In this study, we show that c-Jun participates in macrophage Ulmenweg 18, 91054 Erlangen, Germany. E-mail address: [email protected] activation by regulating the expression pattern of pro- and anti- The online version of this article contains supplemental material. inflammatory genes upon the stimulation with diverse Th1 or Abbreviations used in this article: AC, apoptotic cell; Arg1, arginase-1; ChIP, chro- Th2 cytokines, pro- or anti-inflammatory stimulations, and mi- matin immunoprecipitation; Cox2, cyclooxygenase-2; GO, Gene Ontology; KEGG, crobial products. Gene Ontology (GO) cluster analysis unravels the Kyoto Encyclopedia of Genes and Genomes; MRI, magnetic resonance imaging. important role of c-Jun in immune pathways and IL production. Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 Two targets of c-Jun identified were the proinflammatory enzyme www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601330 2 c-Jun PROMOTES INFLAMMATORY MACROPHAGE SIGNALING cyclooxygenase-2 (Cox2, also known as PG-endoperoxide syn- Western blot analysis thase 2) and the anti-inflammatory enzyme arginase-1 (Arg1). Cells were lysed using Frackelton buffer (10 mM Tris, 50 mM NaCl, 30 mM Using two conditionally deleted c-Jun mice, controlled under the NaPPi, 50 mM NaF, 1% Triton X-100) supplemented with protease inhibitor Mx-1 or the lysozyme 2 promoter, named c-JunDMx or c-JunDLysM, mixture (cOmplete ULTRA; Roche, Basel) followed by three freeze and respectively, we confirmed the direct activation of Cox2 and the thaw cycles in liquid nitrogen. Afterward, lysates were boiled for 5 min in 3 3 6 indirect inhibition of Arg1 by c-Jun. Moreover, using the K/BxN 1 Laemmli buffer and centrifuged. Cell extracts from 0.25 10 mac- rophages were separated by NaDodSO4-PAGE on a 10% acrylamide gel. arthritis model, we showed reduced joint inflammation in c-Jun– Semidry immunoblotting was carried out on polyvinylidene difluoride deficient mice by histological analyses and in vivo magnetic res- membrane, which was further incubated overnight at 4˚C with rabbit anti- onance imaging (MRI). Finally, we confirmed the direct binding mouse c-Jun (1:1000; Cell Signaling Technology, Leiden, the Nether- of c-Jun on the Cox2 promoter in macrophages through chromatin lands), rabbit anti-mouse GAPDH (1:5000; Cell Signaling Technology), and mouse anti-mouse b-actin Ab (1:5000; Sigma-Aldrich, St. Louis, MO)
Load more

Recommended publications
  • Peripheral Mononuclear Blood Cells Contribute to The
    Genes Nutr (2015) 10:11 DOI 10.1007/s12263-015-0460-8 RESEARCH PAPER Peripheral mononuclear blood cells contribute to the obesity- associated inflammatory state independently of glycemic status: involvement of the novel proinflammatory adipokines chemerin, chitinase-3-like protein 1, lipocalin-2 and osteopontin 1,2,3 1,2,3 1,2,3 Victoria Catala´n • Javier Go´mez-Ambrosi • Amaia Rodrı´guez • 1,2,3 2,4 3,5 2,3,6 Beatriz Ramı´rez • Vı´ctor Valentı´ • Rafael Moncada • Camilo Silva • 2,6 1,2,3,6 Javier Salvador • Gema Fru¨hbeck Received: 24 December 2014 / Accepted: 28 March 2015 / Published online: 14 April 2015 Ó Springer-Verlag Berlin Heidelberg 2015 Abstract Inflammation is a critical contributor to the including chemerin, chitinase-3-like protein 1 (YKL-40), pathogenesis of metabolic disorders with adipose tissue lipocalin-2 (LCN-2) and osteopontin (OPN), and their being crucial in the inflammatory response by releasing circulating concentrations were also determined by ELISA. multiple adipokines with either pro- or anti-inflammatory We show, for the first time, that PBMC gene expression activities with potential functions as metabolic regulators. levels of chemerin (P \ 0.0001), chitinase-3-like protein 1 Peripheral blood mononuclear cells (PBMC) have been (P = 0.010), lipocalin-2 (P \ 0.0001) and osteopontin proposed as representative of the inflammatory status in (P \ 0.0001) were strongly upregulated in obesity inde- obesity. The aim of the present study was to evaluate the pendently of the glycemic state. Circulating concentrations contribution of PBMC to the obesity-associated chronic of these adipokines followed the same trend being sig- inflammation analyzing the expression of novel adipokines.
    [Show full text]
  • Microglia Emerge from Erythromyeloid Precursors Via Pu.1- and Irf8-Dependent Pathways
    ART ic LE S Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways Katrin Kierdorf1,2, Daniel Erny1, Tobias Goldmann1, Victor Sander1, Christian Schulz3,4, Elisa Gomez Perdiguero3,4, Peter Wieghofer1,2, Annette Heinrich5, Pia Riemke6, Christoph Hölscher7,8, Dominik N Müller9, Bruno Luckow10, Thomas Brocker11, Katharina Debowski12, Günter Fritz1, Ghislain Opdenakker13, Andreas Diefenbach14, Knut Biber5,15, Mathias Heikenwalder16, Frederic Geissmann3,4, Frank Rosenbauer6 & Marco Prinz1,17 Microglia are crucial for immune responses in the brain. Although their origin from the yolk sac has been recognized for some time, their precise precursors and the transcription program that is used are not known. We found that mouse microglia were derived from primitive c-kit+ erythromyeloid precursors that were detected in the yolk sac as early as 8 d post conception. + lo − + − + These precursors developed into CD45 c-kit CX3CR1 immature (A1) cells and matured into CD45 c-kit CX3CR1 (A2) cells, as evidenced by the downregulation of CD31 and concomitant upregulation of F4/80 and macrophage colony stimulating factor receptor (MCSF-R). Proliferating A2 cells became microglia and invaded the developing brain using specific matrix metalloproteinases. Notably, microgliogenesis was not only dependent on the transcription factor Pu.1 (also known as Sfpi), but also required Irf8, which was vital for the development of the A2 population, whereas Myb, Id2, Batf3 and Klf4 were not required. Our data provide cellular and molecular insights into the origin and development of microglia. Microglia are the tissue macrophages of the brain and scavenge dying have the ability to give rise to microglia and macrophages in vitro cells, pathogens and molecules using pattern recognition receptors and in vivo under defined conditions.
    [Show full text]
  • Semaphorin7a Promotes Tumor Growth and Exerts a Pro-Angiogenic Effect in Macrophages of Mammary Tumor-Bearing Mice
    ORIGINAL RESEARCH ARTICLE published: 05 February 2014 doi: 10.3389/fphys.2014.00017 Semaphorin7A promotes tumor growth and exerts a pro-angiogenic effect in macrophages of mammary tumor-bearing mice Ramon Garcia-Areas 1, Stephania Libreros 1, Samantha Amat 1, Patricia Keating 2, Roberto Carrio 3, Phillip Robinson 4, Clifford Blieden 5 and Vijaya Iragavarapu-Charyulu 1* 1 Tumor Immunology, Department of Biomedical Sciences, Florida Atlantic University, Boca Raton, FL, USA 2 Immunology, Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL, USA 3 Tumor Immunology, Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA 4 Department of Clinical Sciences, Florida Atlantic University, Boca Raton, FL, USA 5 Department of Pathology and Laboratory Medicine, Jackson Memorial Hospital, University of Miami Miller School of Medicine, Miami, FL, USA Edited by: Semaphorins are a large family of molecules involved in axonal guidance during the Michal A. Rahat, Technion - Israel development of the nervous system and have been recently shown to have both Institute for Technology, Israel angiogenic and anti-angiogenic properties. Specifically, semaphorin 7A (SEMA7A) has Reviewed by: been reported to have a chemotactic activity in neurogenesis and to be an immune Andrea Foskett, Texas A&M Health α β Science Center, USA modulator through 1 1integrins. SEMA7A has been shown to promote monocyte Jincai Luo, The University of Tokyo, chemotaxis and induce them to produce proinflammatory mediators. In this study we Japan explored the role of SEMA7A in a murine model of breast cancer. We show that SEMA7A Zahava Vadasz, Bnai-Zion Medical is highly expressed by DA-3 murine mammary tumor cells in comparison to normal Center, Israel mammary cells (EpH4), and that peritoneal elicited macrophages from mammary tumor- *Correspondence: Vijaya Iragavarapu-Charyulu, Tumor bearing mice also express SEMA7A at higher levels compared to those derived from Immunology, Department of normal mice.
    [Show full text]
  • Genome-Wide Analysis Identifies Critical DNA Methylations Within
    Chen et al. J Transl Med (2021) 19:73 https://doi.org/10.1186/s12967-021-02740-6 Journal of Translational Medicine RESEARCH Open Access Genome-wide analysis identifes critical DNA methylations within NTRKs genes in colorectal cancer Zijian Chen1,3† , Zenghong Huang2,3†, Yanxin Luo2,3, Qi Zou3,4, Liangliang Bai3, Guannan Tang3, Xiaolin Wang3, Guangwen Cao5, Meijin Huang2,3, Jun Xiang1* and Huichuan Yu3* Abstract Background: Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers. We aimed to investigate the methylation and expression profles and prognostic value of NTRKs gene in colorectal cancer (CRC). Methods: An analysis of DNA methylation and expression profles in CRC patients was performed to explore the critical methylations within NTRKs genes. The methylation marker was validated in a retrospectively collected cohort of 229 CRC patients and tested in other tumor types from TCGA. DNA methylation status was determined by quantita- tive methylation-specifc PCR (QMSP). Results: The profles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression. We identifed a specifc methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC. NTRK3 promoter methylation showed independently predictive value for survival outcome in the validation cohort (P 0.004, HR 2.688, 95% CI [1.355, 5.333]). Based on this, a nomogram predicting survival outcome was developed with= a C-index of 0.705. Furthermore, the addition of NTRK3 promoter methylation improved the performance of currently-used prognostic model (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P 0.032).
    [Show full text]
  • Chitinase 3-Like-1, a Novel Regulator of Th1/CTL Responses, As a Therapeutic Target for Increasing Anti-Tumor Immunity
    BMB Rep. 2018; 51(5): 207-208 BMB www.bmbreports.org Reports Perspective Chitinase 3-like-1, a novel regulator of Th1/CTL responses, as a therapeutic target for increasing anti-tumor immunity Do-Hyun Kim1,2 & Je-Min Choi1,2,* 1Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 04763, 2Research Institute for Natural Sciences, Hanyang University, Seoul 04763, Korea Chitinase-Like Proteins (CLPs) are an evolutionarily conserved Chitinase is an enzyme that degrades chitin macromolecules, protein which lose their enzymatic activity for degrading chitin which are long-chain polymers of N-acetylglucosamine, a macromolecules. Chitinase-3-like-1 (Chi3l1) is a type of CLP component of cell walls in fungi and the exoskeletons of that is highly expressed in epithelial cells, macrophages, etc., arthropods. Surprisingly, several chitinase and chitinase-like and is known to have correlations with type 2 inflammation proteins (CLPs) have been identified in mammals, and their and cancer. Although the increased level of Chi3l1 in the expression is upregulated in various inflammatory diseases and blood was reported in various disease patients, the function of tumors. Ym1/2 (Chi3l3, Chi3l4) are well-known CLPs as Chi3l1 in adaptive immunity has been totally unknown. markers of alternative activated macrophages and contributors Recently, we found that Chi3l1 is expressed in T cells and has to allergic diseases. A recent study suggests that these CLPs a negative regulatory role in T-cell activation and proliferation. promote T-cell mediated-IL-17 production and neutrophilia A genetic ablation study of Chi3l1 in T cells showed in parasite infection.
    [Show full text]
  • Curriculum Vitae
    Revised 08/14/2019 Yang Zhou, Ph.D. CURRICULUM VITAE NAME Yang Zhou, Ph.D. DATE OF BIRTH March 11, 1983 CITIZENSHIP Chinese (U.S. Permanent Resident) CURRENT POSITION Assistant Professor of Molecular Microbiology & Immunology Division of Biology and Medicine, Brown University Sidney Frank Hall, Room 258 Box G-B5, 185 Meeting Street Providence, RI 02912 401-863-5933 Email: [email protected] ACADEMIC APPOINTMENTS 07/01/2014 Assistant Professor Department of Molecular Microbiology and Immunology Division of Biology and Medicine, Brown University Providence, RI 09/01/2011 Associate Research Scientist Section of Pulmonary, Critical Care and Sleep Medicine Department of Internal Medicine Yale University School of Medicine, New Haven, CT EDUCATION 2010-2011 Postdoctoral Associate Section of Pulmonary and Critical Care Medicine Department of Internal Medicine Yale University School of Medicine, New Haven, CT Mentor, Jack A. Elias, M.D. 2005-2010 Ph.D. in Biochemistry and Molecular Biology The University of Texas Health Sciences Center Houston, TX Advisor, Michael R. Blackburn, Ph.D. 2001-2005 B.S. in Biochemistry Nanjing University, Nanjing, China 1 Revised 08/14/2019 Yang Zhou, Ph.D. AWARDS AND HONORS 2013-2014 American Thoracic Society Abstract Scholarship Award 2011 American Thoracic Society Hermansky-Pudlak Syndrome Network Research Award 2010 President’s Research Scholarship The University of Texas Health Science Center 2010 Graduate Student Education Committee Poster Competition The University of Texas Health Sciences Center 2009 Dean’s
    [Show full text]
  • Dipeptidase As Biomarkers Associated With
    Cantó et al. Journal of Neuroinflammation 2014, 11:181 JOURNAL OF http://www.jneuroinflammation.com/content/11/1/181 NEUROINFLAMMATION RESEARCH Open Access Validation of semaphorin 7A and ala-β-his- dipeptidase as biomarkers associated with the conversion from clinically isolated syndrome to multiple sclerosis Ester Cantó1, Mar Tintoré1, Luisa Maria Villar2, Eva Borrás3, Jose Carlos Álvarez-Cermeño2, Cristina Chiva3, Eduard Sabidó3, Alex Rovira4, Xavier Montalban1 and Manuel Comabella1,5* Abstract Background: In a previous proteomics study using pooled cerebrospinal fluid (CSF) samples, we proposed apolipoprotein AI, apolipoprotein AIV, vitronectin, plasminogen, semaphorin 7A, and ala-β-his-dipeptidase as candidate biomarkers associated with the conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndromes (CIS). Here, we aimed to validate these results in individual CSF samples using alternative techniques. Methods: In a first replication study, levels of apolipoproteins AI and AIV, vitronectin, and plasminogen were measured by ELISA in CSF and serum of 56 CIS patients (29 patients who converted to CDMS (MS converters) and 27 patients who remained with CIS during follow-up (MS non-converters)) and 26 controls with other neurological disorders. Semaphorin 7A and ala-β-his-dipeptidase levels were determined by selected reaction monitoring (SRM) in CSF of 36 patients (18 MS converters, 18 non-converters) and 20 controls. In a second replication study, apolipoprotein AI levels were measured by ELISA in CSF of 74 CIS patients (47 MS converters, 27 non-converters) and 50 individual controls, and levels of semaphorin 7A and ala-beta-his-dipeptidase were determined by SRM in 49 patients (24 MS converters, 25 non-converters) and 22 controls.
    [Show full text]
  • Chitinase-3-Like 1 Protein (CHI3L1) Locus Influences Cerebrospinal Fluid Levels of YKL-40 Yuetiva Deming1 , Kathleen Black1, David Carrell1, Yefei Cai1, Jorge L
    Deming et al. BMC Neurology (2016) 16:217 DOI 10.1186/s12883-016-0742-9 RESEARCH ARTICLE Open Access Chitinase-3-like 1 protein (CHI3L1) locus influences cerebrospinal fluid levels of YKL-40 Yuetiva Deming1 , Kathleen Black1, David Carrell1, Yefei Cai1, Jorge L. Del-Aguila1, Maria Victoria Fernandez1, John Budde1, ShengMei Ma1, Benjamin Saef1, Bill Howells1, Sarah Bertelsen2, Kuan-lin Huang3, Courtney L. Sutphen4, Rawan Tarawneh4,5,6, Anne M. Fagan4,5,6, David M. Holtzman4,5,6,7, John C. Morris4,5,6,7, Alison M. Goate2, Joseph D. Dougherty1,3 and Carlos Cruchaga1,6* Abstract Background: Alzheimer’s disease (AD) pathology appears several years before clinical symptoms, so identifying ways to detect individuals in the preclinical stage is imperative. The cerebrospinal fluid (CSF) Tau/Aβ42 ratio is currently the best known predictor of AD status and cognitive decline, and the ratio of CSF levels of chitinase-3-like 1 protein (CHI3L1, YKL-40) and amyloid beta (Aβ42) were reported as predictive, but individual variability and group overlap inhibits their utility for individual diagnosis making it necessary to find ways to improve sensitivity of these biomarkers. Methods: We used linear regression to identify genetic loci associated with CSF YKL-40 levels in 379 individuals (80 cognitively impaired and 299 cognitively normal) from the Charles F and Joanne Knight Alzheimer’s Disease Research Center. We tested correlations between YKL-40 and CSF Tau/Aβ42 ratio, Aβ42, tau, and phosphorylated tau (ptau181). We used studentized residuals from a linear regression model of the log-transformed, standardized protein levels and the additive reference allele counts from the most significant locus to adjust YKL-40 values and tested the differences in correlations with CSF Tau/Aβ42 ratio, Aβ42, tau, and ptau181.
    [Show full text]
  • A Dual Cis-Regulatory Code Links IRF8 to Constitutive and Inducible Gene Expression in Macrophages
    Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages Alessandra Mancino,1,3 Alberto Termanini,1,3 Iros Barozzi,1 Serena Ghisletti,1 Renato Ostuni,1 Elena Prosperini,1 Keiko Ozato,2 and Gioacchino Natoli1 1Department of Experimental Oncology, European Institute of Oncology (IEO), 20139 Milan, Italy; 2Laboratory of Molecular Growth Regulation, Genomics of Differentiation Program, National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland 20892, USA The transcription factor (TF) interferon regulatory factor 8 (IRF8) controls both developmental and inflammatory stimulus-inducible genes in macrophages, but the mechanisms underlying these two different functions are largely unknown. One possibility is that these different roles are linked to the ability of IRF8 to bind alternative DNA sequences. We found that IRF8 is recruited to distinct sets of DNA consensus sequences before and after lipopolysaccharide (LPS) stimulation. In resting cells, IRF8 was mainly bound to composite sites together with the master regulator of myeloid development PU.1. Basal IRF8–PU.1 binding maintained the expression of a broad panel of genes essential for macrophage functions (such as microbial recognition and response to purines) and contributed to basal expression of many LPS-inducible genes. After LPS stimulation, increased expression of IRF8, other IRFs, and AP-1 family TFs enabled IRF8 binding to thousands of additional regions containing low-affinity multimerized IRF sites and composite IRF–AP-1 sites, which were not premarked by PU.1 and did not contribute to the basal IRF8 cistrome.
    [Show full text]
  • Genequery™ Human Stem Cell Transcription Factors Qpcr Array
    GeneQuery™ Human Stem Cell Transcription Factors qPCR Array Kit (GQH-SCT) Catalog #GK125 Product Description ScienCell's GeneQuery™ Human Stem Cell Transcription Factors qPCR Array Kit (GQH-SCT) surveys a panel of 88 transcription factors related to stem cell maintenance and differentiation. Transcription factors are proteins that can regulate target gene transcription level by binding to specific regions of the genome known as enhancers or silencers. Brief examples of how genes may be grouped according to their functions are shown below: • Pluripotency transcription factors: NANOG, POU5F1, SOX2 • Embryonic development: EOMES, FOXC2/D3/O1, HOXA9/A10, KLF2/5, LIN28B, MAX, PITX2, SMAD1, TBX5, ZIC1 • Germ layer formation and differentiation: FOXA2, GATA6, HAND1, ISL1, KLF4, SMAD2, SOX9 • Organ morphogenesis: EZH2, HOXA11/B3/B5/C9, MSX2, MYC, PAX5/8, VDR • Angiogenesis: CDX2, JUN, NR2F2, RUNX1, WT1 • Hematopoiesis and osteogenesis: EGR3, ESR1, GATA1/2/3, GLI2, NFATC1, PAX9, RB1, SOX6, SP1, STAT1 • Neural stem cell maintenance and differentiation: ATF2, CREB1, FOSB, FOXO3, HES1, HOXD10, MCM2/7, MEF2C, NEUROD1/G1, OLIG1/2, PAX3/6, POU4F1, PPARG, SMAD3/4, SNAI1, STAT3 Note : all gene names follow their official symbols by the Human Genome Organization Gene Nomenclature Committee (HGNC). GeneQuery™ qPCR array kits are qPCR ready in a 96-well plate format, with each well containing one primer set that can specifically recognize and efficiently amplify a target gene's cDNA. The carefully designed primers ensure that: (i) the optimal annealing temperature in qPCR analysis is 65°C (with 2 mM Mg 2+ , and no DMSO); (ii) the primer set recognizes all known transcript variants of target gene, unless otherwise indicated; and (iii) only one gene is amplified.
    [Show full text]
  • CHI3L1, NTRK2, 1P/19Q and IDH Status Predicts Prognosis in Glioma
    cancers Article CHI3L1, NTRK2, 1p/19q and IDH Status Predicts Prognosis in Glioma 1,2 1, 3,4, 5 Elise Deluche , Barbara Bessette y , Stephanie Durand y , François Caire , Valérie Rigau 6, Sandrine Robert 1,7 , Alain Chaunavel 1,7, Lionel Forestier 3, François Labrousse 1,7, Marie-Odile Jauberteau 1,8, Karine Durand 1,7 and Fabrice Lalloué 1,* 1 EA3842 CAPTuR, Faculty of Medicine, University of Limoges, 2 Rue du Docteur Marcland, 87025 Limoges, France; [email protected] (E.D.); [email protected] (B.B.); [email protected] (S.R.); [email protected] (A.C.); [email protected] (F.L.); [email protected] (M.-O.J.); [email protected] (K.D.) 2 Department of Medical Oncology, Limoges University Hospital, 2 rue Martin Luther King, 87042 Limoges, France 3 Bioinformatics Team, BISCEM Platform, CBRS, University of Limoges, 2 rue du Docteur Marcland, 87025 Limoges, France; [email protected] (S.D.); [email protected] (L.F.) 4 EA7500 PEREINE, University of Limoges, 123 av. Albert Thomas, 87060 Limoges, France 5 Department of Neurosurgery, Limoges University Hospital, 2 rue Martin Luther King, 87042 Limoges, France; [email protected] 6 Department of Neuropathology and INSERM U1051, Hospital Saint Eloi—Gui de Chauliac, 80 av. Augustin Fliche, 34090 Montpellier, France; [email protected] 7 Department of Pathology, Limoges University Hospital, 2 rue Martin Luther King, 87042 Limoges, France 8 Department of Immunology, Limoges University Hospital, 2 rue Martin Luther King, 87042 Limoges, France * Correspondence: [email protected]; Tel.: +33-5-55-43-59-29 These authors contributed equally to this work.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]