DOCSLIB.ORG

Cross-Disease Innate Gene Signature: Emerging Diversity and Abundance in RA Comparing to SLE and Ssc

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cross-Disease Innate Gene Signature: Emerging Diversity and Abundance in RA Comparing to SLE and Ssc Hindawi Journal of Immunology Research Volume 2019, Article ID 3575803, 10 pages https://doi.org/10.1155/2019/3575803 Research Article Cross-Disease Innate Gene Signature: Emerging Diversity and Abundance in RA Comparing to SLE and SSc Anna Petrackova,1 Pavel Horak,2 Martin Radvansky,3 Martina Skacelova,2 Regina Fillerova,1 Milos Kudelka,3 Andrea Smrzova,2 Frantisek Mrazek,1 and Eva Kriegova 1 1Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital, Olomouc, Czech Republic 2Department of Internal Medicine III-Nephrology, Rheumatology and Endocrinology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital, Olomouc, Czech Republic 3Faculty of Electrical Engineering and Computer Science, Department of Computer Science, VSB-Technical University of Ostrava, Ostrava, Czech Republic Correspondence should be addressed to Eva Kriegova; [email protected] Received 3 April 2019; Accepted 12 June 2019; Published 16 July 2019 Academic Editor: Darius Widera Copyright © 2019 Anna Petrackova et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Overactivation of the innate immune system together with the impaired downstream pathway of type I interferon-responding genes is a hallmark of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc). To date, limited data on the cross-disease innate gene signature exists among those diseases. We compared therefore an innate gene signature of Toll-like receptors (TLRs), seven key members of the interleukin (IL)1/IL1R family, and CXCL8/IL8 in peripheral blood mononuclear cells from well-defined patients with active stages of RA (n =36, DAS28 ≥ 3 2), SLE (n =28, SLEDAI > 6), and SSc (n =22, revised EUSTAR index > 2 25). Emerging diversity and abundance of the innate signature in RA patients were detected: RA was characterized by the upregulation of TLR3, TLR5, IL1RAP/IL1R3, IL18R1, and SIGIRR/IL1R8 when compared to SSc (Pcorr <002) and of TLR2, TLR5, and SIGIRR/IL1R8 when compared to SLE (Pcorr <002). Applying the association rule analysis, six rules (combinations and expression of genes describing disease) were identified for RA (most frequently included high TLR3 and/or IL1RAP/IL1R3) and three rules for SLE (low IL1RN and IL18R1) and SSc (low TLR5 and IL18R1). This first cross-disease study identified emerging heterogeneity in the innate signature of RA patients with many upregulated innate genes compared to that of SLE and SSc. 1. Introduction Although the emerging role of the innate immunity in the pathogenesis of RA, SLE, and SSc has been demonstrated, Rheumatoid arthritis (RA), systemic lupus erythematosus there is no data on the cross-disease innate gene signature (SLE), and systemic sclerosis (SSc) are systemic autoimmune as well as its heterogeneity among those diseases yet. Numer- diseases characterized by overactivation of the innate ous studies on individual innate immunity members in RA, immune system together with impaired downstream path- SLE, and SSc showed the crucial role of Toll-like receptors way of type I interferon- (IFN-) responding genes (IFN sig- (TLRs) and IL1 family [5, 6]. Notable examples of common nature). Nevertheless, a certain heterogeneity in the IFN innate pathways are (i) the involvement of the adapter pro- signature among those diseases has been recognized, and tein MyD88 which is required for signal transduction by some patients even lack its presence [1–4]. TLRs and receptors of the IL1 family, (ii) the activation of 2 Journal of Immunology Research Table 1: Demographic and clinical characteristics of enrolled patients. RA (n =36) SLE (n =28) SSc (n =22) Female/male 26/10 24/4 15/7 Age (years) mean (min-max) 57.5 (39-80) 40.1 (19-67) 58.0 (38-77) Duration of the disease (years) mean (min-max) 18.1 (9-50) 10.0 (1-20) 5.4 (0-21) Medications (% (n)) Steroids 89 (32) 82 (23) 96 (21) NSAIDs 78 (28) 14 (4) 0 (0) Methotrexate 83 (30) 14 (4) 9 (2) ∗ Other DMARDs 36 (13) 100 (28) 73 (16) Biologics 39 (14) 0 (0) 0 (0) Relative white blood count (%) Lymphocytes (mean (95% CI)) 24.9 (20.5-29.3) 22.9 (18.5-27.3) 21.4 (17.5-25.4) Neutrophils (mean (95% CI)) 62.9 (57.9-67.9) 67.1 (61.6-72.6) 67.3 (62.5-72.2) Monocytes (mean (95% CI)) 8.9 (7.9-9.9) 8.5 (7.1-9.9) 9.2 (7.9-10.4) NSAIDs: nonsteroidal anti-inflammatory drugs; DMARDs: disease-modifying antirheumatic drugs; CI: confidence interval. ∗Other DMARDs taken were hydroxychloroquine (RA/SLE/SSc; n = 3/26/0), leflunomide (8/0/0), sulfasalazine (2/0/0), azathioprine (0/8/12), mycophenolate mofetil (0/6/0), cyclophosphamide (0/3/3), and cyclosporine (0/1/1). the type I IFN, and (iii) the presence of endogenous TLR criteria for SSc, respectively [15]. To exclude heterogeneity ligands [7]. Besides shared innate pathways, disease-specific due to the activity and inactivity of the diseases, only cases molecular and cellular mechanisms exist. In SLE, recent evi- with active phenotypes of the disease classified according to dence has suggested a close relationship between the endoso- common activity scores (Disease Activity Score in 28 joints mal TLR activation and the disease onset [8, 9] with an (DAS28), SLE Disease Activity Index (SLEDAI), and revised essential role of endosomal TLRs in the generation of anti- European Scleroderma Trials and Research group (EUSTAR) nuclear antibodies and type I IFNs [10]. In RA, abundant acti- index) were included: RA (n =36, DAS28 ≥ 3 2), SLE (n =28, vation of individual members of TLR and IL1 families was SLEDAI > 6), and SSc (n =22, revised EUSTAR index > 2 25). already evidenced with a proposed role for exogenous TLR The demographic and clinical features, used medication, ligands in the disease onset (i.e., Proteus infection of urinary duration of disease, and relative white blood count are tract, Epstein-Barr virus, and parvovirus B19) and for endog- described in Table 1. Distribution of lymphocyte, neutrophil, enous ligands in self-sustaining of the inflammatory loop and monocyte counts did not differ between studied patient’s [5, 11]. In SSc, signaling via TLR is increasingly recognized groups (P >005). The healthy control cohort consisted of 77 as a key player driving the persistent fibrotic response and is subjects (mean age 51 yrs, min-max 24-90 yrs, female/male linked to the activity of TGF-β; however, the pathological role 58/19) out of which were formed three age-/gender-matched of TLRs and their ligands in SSc still remains unclear [12]. groups for each disease: 63 controls for RA (mean age 56 yrs, We undertook this study to elucidate the underlying dif- min-max 41-90 yrs, female/male 45/18), 33 controls for SLE ferences in the innate immunity signature across three major (40, 24-50, 27/6, respectively), and 48 controls for SSc (58, autoimmune disorders using multivariate analysis. This first 48-90, 34/14, respectively). In all healthy subjects, presence cross-disease analysis of the innate gene expression signature of inflammatory autoimmune diseases in first or second of 10 TLRs, 7 key members of the IL1/IL1R family, and degree relatives, recent vaccination, infection, and usage of interleukin 8 (CXCL8) in peripheral blood mononuclear immunosuppressive drugs were excluded by questionnaire. cells (PBMC) from patients with active SLE, RA, and SSc The patients and control subjects provided written revealed emerging diversity and abundance in RA compared informed consent about the usage of peripheral blood for to SLE and SSc. Our study contributes to further understand- the purpose of this study, which was approved by the ing of the innate signature underlying the immunopathology ethics committee of the University Hospital and Palacký of major autoimmune diseases, with special emphases to University Olomouc. discriminate shared and disease-specific expression patterns. 2.2. Sample Processing and Real-Time Reverse Transcription- 2. Materials and Methods Polymerase Chain Reaction (qRT-PCR). The PBMC were iso- lated from the peripheral blood collected in K3EDTA tubes 2.1. Study Subjects. The study cohort consisted of 86 Cauca- by Ficoll density gradient centrifugation (Sigma-Aldrich, sian patients with autoimmune diseases from a single rheuma- Germany) and stored in TRI Reagent (Sigma-Aldrich, Ger- ° tology center in Olomouc, Moravia region of Czech Republic. many) at −80 C until analysis. Total RNA was extracted All enrolled RA/SLE/SSc patients met the 2010 ACR/EULAR using a Direct-zol RNA kit (Zymo Research, USA) according classification criteria for RA [13], the ACR classification cri- to the manufacturer’s recommendations. After reverse tran- teria for SLE [14], and the 2013 ACR/EULAR classification scription with a Transcriptor First Strand cDNA Synthesis Journal of Immunology Research 3 TLR5 SIGIRR TLR2 0.25 0.4 0.7 P = 0.02 P = 0.02 P = 0.009 corr 0.3 corr 0.20 corr 0.6 0.2 0.15 0.5 0.15 0.08 0.4 0.10 0.06 0.3 0.04 0.2 0.05 mRNA relative expression relative mRNA mRNA relative expression relative mRNA 0.02 expression relative mRNA 0.1 0.00 0.0 0.00 RA SLE RA SLE RA SLE (a) IL1RAP TLR5 IL18R1 0.4 P = 3 × 10-6 P = 0.0001 P = 0.0001 0.10 corr corr corr 0.2 0.03 0.05 0.10 0.020 0.08 0.02 0.015 0.06 0.010 0.04 0.01 mRNA relative expression relative mRNA 0.005 expression relative mRNA 0.02 expression relative mRNA 0.000 0.00 0.00 RA SSc RA SSc RA SSc SIGIRR TLR3 0.020 P = 0.003 0.7 corr Pcorr = 0.007 0.6 0.016 0.5 0.012 0.4 0.3 0.008 0.2 0.004 mRNA relative expression relative mRNA 0.1 expression relative mRNA 0.0 0.000 RA SSc RA SSc (b) IL1R1 0.03 P corr = 0.005 0.012 0.009 0.006 0.003 mRNA relative expression relative mRNA 0.000 SSc SLE (c) Figure 1: Relative mRNA expression levels of genes differentially expressed in (a) RA vs.
Load more

Recommended publications
  • Mechanisms of Single Ig Il-1-Related Receptor Mediated Suppression of Colon Tumorigenesis
    MECHANISMS OF SINGLE IG IL-1-RELATED RECEPTOR MEDIATED SUPPRESSION OF COLON TUMORIGENESIS by JUNJIE ZHAO Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor Xiaoxia Li, Ph.D. Department of Molecular Medicine CASE WESTERN RESERVE UNIVERSITY May 2016 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of Junjie Zhao Candidate for the degree of Ph.D.* Committee Chair Brian Cobb, Ph.D. Research Advisor Xiaoxia Li, Ph.D. Committee Member Donal Luse, Ph.D. Committee Member Booki Min, Ph.D. Committee Member Bo Shen, M.D. Date of Defense March 8, 2016 *We also certify that written approval has been obtained for any proprietary contained therein. ii TABLE OF CONTENTS LIST OF TABLES ................................................................................................................. 1 LIST OF FGIURES ................................................................................................................ 2 ABSTRACT ........................................................................................................................... 4 Chapter 1 Introduction To The Role Of Toll-Like Receptor And Interleukin 1 Receptors In Colon Tumorigenesis SIGIRR, A NEGATIVE REGULATOR OF TLR-IL-1R SIGNALING .............................................. 8 TLR-IL-1R SUPERFAMILY AND COLON TUMORIGENESIS .................................................... 10 SIGIRR IN INTESTINAL EPITHELIAL CELLS ........................................................................
    [Show full text]
  • Interleukin-18 As a Therapeutic Target in Acute Myocardial Infarction and Heart Failure
    Interleukin-18 as a Therapeutic Target in Acute Myocardial Infarction and Heart Failure Laura C O’Brien,1 Eleonora Mezzaroma,2,3,4 Benjamin W Van Tassell,2,3,4 Carlo Marchetti,2,3 Salvatore Carbone,2,3 Antonio Abbate,1,2,3 and Stefano Toldo2,3 1Department of Physiology and Biophysics, 2Victoria Johnson Research Laboratories, and 3Virginia Commonwealth University Pauley Heart Center, School of Medicine, and 4Pharmacotherapy and Outcome Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States of America Interleukin 18 (IL-18) is a proinflammatory cytokine in the IL-1 family that has been implicated in a number of disease states. In animal models of acute myocardial infarction (AMI), pressure overload, and LPS-induced dysfunction, IL-18 regulates cardiomy- ocyte hypertrophy and induces cardiac contractile dysfunction and extracellular matrix remodeling. In patients, high IL-18 levels correlate with increased risk of developing cardiovascular disease (CVD) and with a worse prognosis in patients with established CVD. Two strategies have been used to counter the effects of IL-18:IL-18 binding protein (IL-18BP), a naturally occurring protein, and a neutralizing IL-18 antibody. Recombinant human IL-18BP (r-hIL-18BP) has been investigated in animal studies and in phase I/II clinical trials for psoriasis and rheumatoid arthritis. A phase II clinical trial using a humanized monoclonal IL-18 antibody for type 2 diabetes is ongoing. Here we review the literature regarding the role of IL-18 in AMI and heart failure and the evidence and challenges of using IL-18BP and blocking IL-18 antibodies as a therapeutic strategy in patients with heart disease.
    [Show full text]
  • Interleukin-18 in Health and Disease
    International Journal of Molecular Sciences Review Interleukin-18 in Health and Disease Koubun Yasuda 1 , Kenji Nakanishi 1,* and Hiroko Tsutsui 2 1 Department of Immunology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan; [email protected] 2 Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-798-45-6573 Received: 21 December 2018; Accepted: 29 January 2019; Published: 2 February 2019 Abstract: Interleukin (IL)-18 was originally discovered as a factor that enhanced IFN-γ production from anti-CD3-stimulated Th1 cells, especially in the presence of IL-12. Upon stimulation with Ag plus IL-12, naïve T cells develop into IL-18 receptor (IL-18R) expressing Th1 cells, which increase IFN-γ production in response to IL-18 stimulation. Therefore, IL-12 is a commitment factor that induces the development of Th1 cells. In contrast, IL-18 is a proinflammatory cytokine that facilitates type 1 responses. However, IL-18 without IL-12 but with IL-2, stimulates NK cells, CD4+ NKT cells, and established Th1 cells, to produce IL-3, IL-9, and IL-13. Furthermore, together with IL-3, IL-18 stimulates mast cells and basophils to produce IL-4, IL-13, and chemical mediators such as histamine. Therefore, IL-18 is a cytokine that stimulates various cell types and has pleiotropic functions. IL-18 is a member of the IL-1 family of cytokines. IL-18 demonstrates a unique function by binding to a specific receptor expressed on various types of cells.
    [Show full text]
  • SIGIRR (CT) Antibody (Pab)
    21.10.2014SIGIRR (CT) antibody (pAb) Rabbit Anti -Human/Mouse SIGIRR (TLR Inhibitor) Instruction Manual Catalog Number PK-AB718-3367 Synonyms SIGIRR Antibody: Description SIGIRR is a member of the Toll-like receptor-interleukin 1 receptor superfamily. Members of this family are defined by the presence of an intracellular Toll-IL-1R (TIR) domain. The Toll-like receptors (TLRs) are signaling molecules that recognize different microbial products during infection and serve as an important link between the innate and adaptive immune responses. SIGIRR was originally identified through database analysis and was shown to have only one Ig domain as opposed to the normal three Ig folds seen in the TIR family. Similar to ST2, another TIR family member, it has been shown to negatively regulate IL-1 receptor and Toll-like receptor signaling. However, SIGIRR inhibits TLR-IL-1R signaling by dimerizing with TLR4, TLR5, TLR9, and IL-1R. It also associates with the down-stream TLR signaling proteins IRAK and TRAF6 in an IL-1- dependent fashion. Quantity 100 µg Source / Host Rabbit Immunogen Rabbit polyclonal SIGIRR antibody was raised against a synthetic peptide corresponding to 15 amino acids at the C-terminus of mouse SIGIRR (Genbank accession No. CAG33619). Purification Method Affinity chromatography purified via peptide column. Clone / IgG Subtype Polyclonal antibody Species Reactivity Human, Mouse Specificity Formulation Antibody is supplied in PBS containing 0.02% sodium azide. Reconstitution During shipment, small volumes of antibody will occasionally become entrapped in the seal of the product vial. For products with volumes of 200 μl or less, we recommend gently tapping the vial on a hard surface or briefly centrifuging the vial in a tabletop centrifuge to dislodge any liquid in the container’s cap.
    [Show full text]
  • Extracellular Forms of IL-37 Inhibit Innate Inflammation in Vitro and in Vivo but Require the IL-1 Family Decoy Receptor IL-1R8
    Extracellular forms of IL-37 inhibit innate inflammation in vitro and in vivo but require the IL-1 family decoy receptor IL-1R8 Suzhao Lia, C. Preston Neffa, Kristina Barbera, Jaewoo Hongb, Yuchun Luoc, Tania Azama, Brent E. Palmera, Mayumi Fujitac, Cecilia Garlandad, Alberto Mantovanid, Soohyun Kimb, and Charles Anthony Dinarelloa,e,1 aDepartment of Medicine, University of Colorado Denver, Aurora, CO 80045; bLaboratory of Cytokine Immunology, Konkuk University, 143-701 Seoul, Republic of Korea; cDepartment of Dermatology, University of Colorado Denver, Aurora, CO 80045; dResearch Institute Humanitas, 20089 Milan, Italy; and eDepartment of Medicine, Radboud University Medical Centre, HB6500 Nijmegen, The Netherlands Contributed by Charles Anthony Dinarello, January 6, 2015 (sent for review November 12, 2014) Similar to IL-1α and IL-33, IL-1 family member IL-37b translocates to Support for an extracellular function for IL-37 comes from early the nucleus and is associated with suppression of innate and adap- studies reported over 10 y ago that demonstrated binding of IL-37 tive immunity. Here we demonstrate an extracellular function of the to the α-chain of IL-18 receptor (IL-18Rα). We therefore hy- IL-37 precursor and a processed form. Recombinant IL-37 precursor pothesized that extracellular IL-37 can function through the reduced LPS-induced IL-6 by 50% (P < 0.001) in highly inflammatory IL-18Rα surface receptor to mediate its anti-inflammatory human blood-derived M1 differentiated macrophages derived from effects but that a negative or decoy receptor would be required. selective subjects but not M2 macrophages. In contrast, a neutraliz- The candidate decoy receptor would likely be IL-1R8 [formerly, – α β ing monoclonal anti IL-37 increased LPS-induced IL-6, TNF and IL-1 single IgG IL-1–related receptor (SIGIRR)] because, similar to P < ( 0.01).
    [Show full text]
  • Toll-Like Receptor Signaling and SIGIRR in Renal Fibrosis Upon Unilateral Ureteral Obstruction
    Toll-Like Receptor Signaling and SIGIRR in Renal Fibrosis upon Unilateral Ureteral Obstruction Veronika Skuginna1., Maciej Lech1., Ramanjaneyulu Allam1, Mi Ryu1, Sebastian Clauss1,2, Heni Eka Susanti1, Christoph Ro¨ mmele1, Cecilia Garlanda3, Alberto Mantovani3, Hans-Joachim Anders1* 1 Department of Nephrology, Medizinische Poliklinik, University of Munich, Munich, Germany, 2 Medizinische Klinik und Poliklinik I Grosshadern, University of Munich, Munich, Germany, 3 Istituto Clinico Humanitas and Fondazione Humanitas per la Ricerca, Rozzano, Italy Abstract Innate immune activation via IL-1R or Toll-like receptors (TLR) contibutes to acute kidney injury but its role in tissue remodeling during chronic kidney disease is unclear. SIGIRR is an inhibitor of TLR-induced cytokine and chemokine expression in intrarenal immune cells, therefore, we hypothesized that Sigirr-deficiency would aggravate postobstructive renal fibrosis. The expression of TLRs as well as endogenous TLR agonists increased within six days after UUO in obstructed compared to unobstructed kidneys while SIGIRR itself was downregulated by day 10. However, lack of SIGIRR did not affect the intrarenal mRNA expression of proinflammatory and profibrotic mediators as well as the numbers of intrarenal macrophages and T cells or morphometric markers of tubular atrophy and interstitial fibrosis. Because SIGIRR is known to block TLR/IL-1R signaling at the level of the intracellular adaptor molecule MyD88 UUO experiments were also performed in mice deficient for either MyD88, TLR2 or TLR9. After UUO there was no significant change of tubular interstitial damage and interstitial fibrosis in neither of these mice compared to wildtype counterparts. Additional in-vitro studies with CD90+ renal fibroblasts revealed that TLR agonists induce the expression of IL-6 and MCP-1/CCL2 but not of TGF-b, collagen-1a or smooth muscle actin.
    [Show full text]
  • Characterization of SIGIRR/IL-1R8 Homolog from Zebrafish Provides
    Characterization of SIGIRR/IL-1R8 Homolog from Zebrafish Provides New Insights into Its Inhibitory Role in Hepatic Inflammation This information is current as of October 3, 2021. Wei Feng, Yi-Feng Gu, Li Nie, Dong-Yang Guo, Li-xin Xiang and Jian-zhong Shao J Immunol 2016; 197:151-167; Prepublished online 20 May 2016; doi: 10.4049/jimmunol.1502334 Downloaded from http://www.jimmunol.org/content/197/1/151 Supplementary http://www.jimmunol.org/content/suppl/2016/05/20/jimmunol.150233 Material 4.DCSupplemental http://www.jimmunol.org/ References This article cites 69 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/197/1/151.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 3, 2021 • No Triage! Every submission reviewed by practicing scientists • 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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Characterization of SIGIRR/IL-1R8 Homolog from Zebrafish Provides New Insights into Its Inhibitory Role in Hepatic Inflammation Wei Feng,*,† Yi-Feng Gu,*,† Li Nie,*,† Dong-Yang Guo,*,† Li-xin Xiang,*,† and Jian-zhong Shao*,†,‡ Single Ig IL-1R–related molecule (SIGIRR, also called IL-1R8 or Toll/IL-1R [TIR]8), a negative regulator for Toll/IL-1R signaling, plays critical roles in innate immunity and various diseases in mammals.
    [Show full text]
  • TIR8/SIGIRR Is an Interleukin-1 Receptor/Toll Like Receptor Family Member with Regulatory Functions in Inflammation and Immunity
    REVIEW ARTICLE published: 29 October 2012 doi: 10.3389/fimmu.2012.00322 TIR8/SIGIRR is an interleukin-1 receptor/toll like receptor family member with regulatory functions in inflammation and immunity Federica Riva1, Eduardo Bonavita2, Elisa Barbati 2,3, Marta Muzio4, Alberto Mantovani 2,3 and Cecilia Garlanda2* 1 Department of Veterinary Science and Public Health, University of Milan, Milan, Italy 2 Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Rozzano, Italy 3 Department of Translational Medicine, University of Milan, Milan, Italy 4 Division of Molecular Oncology, Ospedale San Raffaele, Milan, Italy Edited by: Interleukin-1R like receptors (ILRs) andTollLike Receptors (TLRs) are key receptors of innate Anna Rubartelli, National Cancer immunity, inflammation, and orientation of the adaptive response. They belong to a super- Research Institute, Italy family characterized by the presence of a conserved intracellular domain, theToll/IL-1R(TIR) Reviewed by: Francesco S. Di Giovine, University of domain, which is involved in the activation of a signaling cascade leading to activation of Sheffield, UK transcription factors associated to inflammation.The activation of inflammatory responses Bernard R. Lauwerys, Université and immunity by ILRs or TLRs signaling is potentially detrimental for the host in acute and catholique de Louvain, Belgium chronic conditions and is tightly regulated at different levels by receptor antagonists, decoy *Correspondence: receptors or signaling molecules, and miRNAs. Recent evidence suggests that the ILRs Cecilia Garlanda, Laboratory of Experimental Immunopathology, family member TIR8 (also known as SIGIRR) is a regulatory protein acting intracellularly to Istituto Clinico Humanitas, Via inhibit ILRs and TLRs signaling. In particular, current evidence suggests that TIR8/SIGIRR Manzoni 113, 20089 Rozzano, Italy.
    [Show full text]
  • Different Roles of Tir8/Sigirr on Toll-Like Receptor Signaling
    original article http://www.kidney-international.org & 2007 International Society of Nephrology Different roles of TIR8/SIGIRR on toll-like receptor signaling in intrarenal antigen-presenting cells and tubular epithelial cells M Lech1, C Garlanda2, A Mantovani2, CJ Kirschning3, D Schlo¨ndorff1 and H-J Anders1 1Nephrological Center, Medical Policlinic, University of Munich, Munich, Germany; 2Istituto Clinico Humanitas and Fondazione Humanitas per la Ricerca, Rozzano, Italy and 3Institute of Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, Munich, Germany Toll-like receptors (TLRs) exist on both myeloid and intrinsic The toll-like receptor (TLR)/interleukin 1 receptor (IL-1R) renal cells contributing to the initiation of innate immunity superfamily has a central role for initiating innate anti- during renal infection with uropathogenic Escherichia coli. microbial immunity and, hence, may contribute to renal Toll–interleukin 1 receptor (IL-1R) (TIR)8/SIGIRR is an orphan pathology in infective pyelonephritis.1,2 In fact, renal tubular receptor of the TLR/IL-1R family, which suppresses TLR epithelial cells express TLR1-4 and -11 and can produce signaling of immune cells and is highly expressed in the proinflammatory cytokines and chemokines in response to kidney. Lack of TIR8/SIGIRR is associated with enhanced renal respective TLR ligands.3–6 Furthermore, renal dendritic cells chemokine signaling upon exposure to lipopolysaccharide contribute to innate immunity in the kidney as they are (LPS). This was because of TIR8/SIGIRR expression on resident activated via TLRs either directly by pathogens or by intrarenal myeloid cells rather than tubular epithelial cells endogenous molecules such as Tamm–Horsfall protein.7 which express it on basolateral and luminal membranes.
    [Show full text]
  • Signalling and Transcriptional Regulation in Inflammatory and Immune Cells: Importance in Lung Biology and Disease
    Eur Respir J 2005; 26: 762–763 DOI: 10.1183/09031936.05.00093305 CopyrightßERS Journals Ltd 2005 EDITORIAL Signalling and transcriptional regulation in inflammatory and immune cells: importance in lung biology and disease K.F. Chung and I.M. Adcock iving cells respond to their external environment and to development is difficult because there are .500 protein signals from other cells by transducing these signals to kinases in the human genome with relatively conserved active L different parts of the cell, particularly to the nucleus. sites [4]. This idea was initiated by RALL and SUTHERLAND [1], with the Beginning in this issue of the European Respiratory Journal (ERJ), concept of cyclic adenosine monophosphate acting as a second a series of articles will be published, detailing how immune messenger to mediate the action of the first messenger that arrived at the cell surface. Much of cell biology is now focused and inflammatory cells respond to external stimuli to on dissecting out signalling pathways from the cell membrane transduce the initial signal, and enhance and perpetuate the to the nucleus and also to other parts of the cell, and on how inflammatory response, and how these signals can be modified the ultimate cellular response will be determined by the in disease and by therapies, with specific relevance to signalling pathways activated. Many signalling pathways respiratory conditions. The signalling pathway can be initiated regulate cell growth, cell survival, cell differentiation, cell by receptor or nonreceptor activation. Receptor activation can migration, cell metabolism and transcriptional regulation of often be linked to the activation of secondary messengers, such inflammatory genes, and it will not be surprising that as the mitogen-activated protein kinases (MAPK) or derangement of these pathways can form the basis of disease phosphoinositol-3 kinase, which could lead to downstream processes involved in inflammation.
    [Show full text]
  • IL1R8 Deficiency Drives Autoimmunity- Associated Lymphoma
    Published OnlineFirst April 24, 2019; DOI: 10.1158/2326-6066.CIR-18-0698 Research Article Cancer Immunology Research IL1R8 Deficiency Drives Autoimmunity- Associated Lymphoma Development Federica Riva1,2, Maurilio Ponzoni3, Domenico Supino2, Maria Teresa Sabrina Bertilaccio4, Nadia Polentarutti2, Matteo Massara2, Fabio Pasqualini2, Roberta Carriero2, Anna Innocenzi3, Achille Anselmo2, Tania Veliz-Rodriguez4, Giorgia Simonetti4, Hans-Joachim Anders5, Federico Caligaris-Cappio4, Alberto Mantovani2,6,7, Marta Muzio4,and Cecilia Garlanda2,6 Abstract Chronic inflammation, including that driven by autoim- opment during the aging of IL1R8-deficient lpr mice, observ- munity, is associated with the development of B-cell lym- ing an increased lymphoid cell expansion that evolved to phomas. IL1R8 is a regulatory receptor belonging to the diffuse large B-cell lymphoma (DLBCL). Molecular and IL1R family, which negatively regulates NF-kBactivation gene-expression analyses showed that the NF-kB pathway À À following stimulation of IL1R or Toll-like receptor family was constitutively activated in Il1r8 / /lpr B splenocytes. members. IL1R8 deficiency is associated with the develop- In human DLBCL, IL1R8 had reduced expression compared ment of severe autoimmune lupus-like disease in lpr mice. with normal B cells, and higher IL1R8 expression was We herein investigated whether concomitant exacerbated associated with a better outcome. Thus, IL1R8 silencing inflammation and autoimmunity caused by the deficiency is associated with increased lymphoproliferation and trans- of IL1R8 could recapitulate autoimmunity-associated lym- formation in the pathogenesis of B-cell lymphomas associ- phomagenesis. We thus monitored B-cell lymphoma devel- ated with autoimmunity. Introduction matory conditions, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and Sjogren syndrome, are prone to develop The association between chronic inflammation and promotion lymphomas, namely, B-cell non-Hodgkin lymphomas (B-NHL; of malignancy was first described in the nineteenth century (1) refs.
    [Show full text]
  • Immune Response Against Chlamydia Trachomatis Via Toll-Like Receptors Is Negatively Regulated by SIGIRR
    University of the Pacific Scholarly Commons Dugoni School of Dentistry Faculty Articles Arthur A. Dugoni School of Dentistry 1-1-2020 Immune response against Chlamydia trachomatis via toll-like receptors is negatively regulated by SIGIRR Mufadhal Al-Kuhlani Fresno City College Graham Lambert Touro University - Nevada Sukumar Pal University of California, Irvine Luis de la Maza University of California, Irvine David M. Ojcius University of the Pacific, California, [email protected] Follow this and additional works at: https://scholarlycommons.pacific.edu/dugoni-facarticles Part of the Dentistry Commons Recommended Citation Al-Kuhlani, M., Lambert, G., Pal, S., de la Maza, L., & Ojcius, D. M. (2020). Immune response against Chlamydia trachomatis via toll-like receptors is negatively regulated by SIGIRR. PLoS ONE, 15(3), DOI: 10.1371/journal.pone.0230718 https://scholarlycommons.pacific.edu/dugoni-facarticles/481 This Article is brought to you for free and open access by the Arthur A. Dugoni School of Dentistry at Scholarly Commons. It has been accepted for inclusion in Dugoni School of Dentistry Faculty Articles by an authorized administrator of Scholarly Commons. For more information, please contact [email protected]. PLOS ONE RESEARCH ARTICLE Immune response against Chlamydia trachomatis via toll-like receptors is negatively regulated by SIGIRR Mufadhal Al-Kuhlani1,2, Graham Lambert3, Sukumar Pal4, Luis de la Maza4, David 2 M. OjciusID * 1 Life Science Department, Fresno City College, Fresno, CA, United States of America, 2 Department
    [Show full text]