DOCSLIB.ORG

IL-1 Secretion Innate T Cell Responses Through Effects On

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
IL-1 Secretion Innate T Cell Responses Through Effects On Autophagy Regulates IL-23 Secretion and Innate T Cell Responses through Effects on IL-1 Secretion This information is current as Celia Peral de Castro, Sarah A. Jones, Clíona Ní Cheallaigh, of September 24, 2021. Claire A. Hearnden, Laura Williams, Jan Winter, Ed C. Lavelle, Kingston H. G. Mills and James Harris J Immunol 2012; 189:4144-4153; Prepublished online 12 September 2012; doi: 10.4049/jimmunol.1201946 Downloaded from http://www.jimmunol.org/content/189/8/4144 Supplementary http://www.jimmunol.org/content/suppl/2012/09/12/jimmunol.120194 Material 6.DC1 http://www.jimmunol.org/ References This article cites 48 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/189/8/4144.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 24, 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 © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Autophagy Regulates IL-23 Secretion and Innate T Cell Responses through Effects on IL-1 Secretion Celia Peral de Castro,*,† Sarah A. Jones,*,† Clı´ona Nı´ Cheallaigh,‡ Claire A. Hearnden,‡ Laura Williams,* Jan Winter,‡ Ed C. Lavelle,†,‡ Kingston H. G. Mills,*,† and James Harris*,† Autophagy controls IL-1b secretion by regulating inflammasome activation and by targeting pro–IL-1b for degradation. In this article, we show that inhibition of autophagy, either with the PI3K inhibitors 3-methyladenine, wortmannin, and LY294002 or with small interfering RNA against autophagy proteins augmented the secretion of IL-23 by human and mouse macrophages and dendritic cells in response to specific TLR agonists. This process occurred at the transcriptional level and was dependent on reactive oxygen species and IL-1R signaling; it was abrogated with an IL-1R antagonist or with IL-1–neutralizing Abs, whereas treatment with either rIL-1a or IL-1b induced IL-23 secretion. Dendritic cells treated with LPS and 3-methyladenine secreted Downloaded from enhanced levels of both IL-1b and IL-23, and supernatants from these cells stimulated the innate secretion of IL-17, IFN-g, and IL-22 by gd T cells. These data demonstrate that autophagy has a potentially pivotal role to play in the induction and regulation of inflammatory responses by innate immune cells, largely driven by IL-1 and its consequential effects on IL-23 secretion. The Journal of Immunology, 2012, 189: 4144–4153. utophagy is a highly conserved homeostatic mechanism oxygen species (ROS), and mitochondrial DNA (10–13). In ad- http://www.jimmunol.org/ that orchestrates the sequestration and degradation of dition, inhibition of autophagy enhances the secretion of IL-1a A damaged or noxious cytosolic constituents, including or- and IL-18 in response to LPS (10). Conversely, autophagosomes ganelles, and regulates the catabolism of macromolecules during have been shown to target both pro–IL-1b and the inflammasome nutrient deprivation. More recently, autophagy has been shown components ASC and NLRP3 within cells, thus directly regulating to regulate inflammation and immune responses to infection. In the production and availability of IL-1b (10, 14). Moreover, both particular, autophagy can mediate the intracellular killing of some IL-1b and IL-1a induce autophagy in macrophages (15), sug- bacteria by macrophages (1) and is involved in the presentation of gesting that these cytokines might regulate their own secretion. Ags via MHC class I and class II molecules (2). Autophagy is These data, together with studies showing that autophagy alters by guest on September 24, 2021 regulated by cytokines; in macrophages, it is induced by IFN-g disease outcomes in animal models of sepsis (10, 11) and colitis and TNF-a (3, 4) and inhibited by IL-4, IL-13, and IL-10 (5‑8). (12), suggest that autophagy is a potent regulator of inflammatory Numerous studies have also demonstrated a role for autophagy responses. Supporting this, polymorphisms in human ATG16L1, in regulating the secretion of cytokines (reviewed in Ref. 9), in- a protein involved in autophagosome formation, have been asso- cluding members of the IL-1 family. ciated with an increased risk of Crohn’s disease (16, 17). Inhibition of autophagy allows the processing and secretion Both IL-1b and IL-1a, as well as IL-18, can drive IL-17 se- of the proinflammatory cytokine IL-1b in response to TLR3 and cretion by Th17 and gd T cells, but only in the presence of IL- TLR4 agonists, and this process may be dependent on TIR do- 23 (18–20). This pathway can drive inflammatory pathologies in main-containing adaptor protein inducing IFN-b (TRIF), reactive multiple autoimmune diseases, including multiple sclerosis and rheumatoid arthritis (21–24), and is important in immunity to in- fection (18, 25, 26). In this study, we demonstrate that inhibition of *Immune Regulation Research Group, School of Biochemistry and Immunology, autophagy promotes the secretion of IL-1a, IL-1b, and IL-23 by Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland; †Immunology macrophages and dendritic cells (DC), which in turn influences the Research Centre, Trinity College, Dublin 2, Ireland; and ‡Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity innate secretion of IL-17, IFN-g, and IL-22 by gd T cells. More- College, Dublin 2, Ireland over, this is dependent on IL-1 and NF-kB signaling, and both IL- Received for publication July 12, 2012. Accepted for publication August 10, 2012. 1a and IL-1b augment IL-23 production. These data demonstrate This work was supported by Science Foundation Ireland as part of the Immunology a potentially pivotal role for autophagy in regulating inflammatory Research Centre, Science Foundation Ireland Strategic Research Cluster (Grant cytokines and innate T cell-driven immune responses. 07/SRC/B1144). Address correspondence and reprint requests to Dr. James Harris, School of Bio- chemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Materials and Methods Dublin 2, Ireland. E-mail address: [email protected] Materials and reagents The online version of this article contains supplemental material. Wortmannin, LY294002, and rapamycin were from Sigma-Aldrich (Poole, Abbreviations used in this article: BMDC, bone marrow-derived dendritic cell; DC, U.K.), and 3-methyladenine (3-MA) was from Sigma-Aldrich or Merck dendritic cell; iBMM, immortalized bone marrow-derived macrophage; IL-1Ra, IL- Millipore (Billerica, MA). Hydrocinnamoyl-L-valyl pyrrolidine (IL-1R an- 1R antagonist; 3-MA, 3-methyladenine; mTOR, mammalian target of rapamycin; poly(I:C), polyinosinic:polycytidylic acid; rh, recombinant human; ROS, reactive tagonist [IL-1Ra]) and BAY 11-7082 (NF-kB inhibitor) were from Merck oxygen species; siRNA, small interfering RNA; TRIF, TIR domain-containing adap- Millipore. LPS from Escherichia coli serotype R515 was from Enzo Life tor protein inducing IFN-b. Sciences (Exeter, U.K.), and polyinosinic:polycytidylic acid [poly(I:C)], R837, and CpG were from InvivoGen (San Diego, CA). PP242 was from Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 Chemdea (Ridgewood, NJ). Recombinant human (rh)IL-1b was from www.jimmunol.org/cgi/doi/10.4049/jimmunol.1201946 The Journal of Immunology 4145 Immunotools (Friesoythe, Germany). Granzyme B-cleaved and full-length propidium iodide (1 mg/ml) for 5 min. A CyAN (DakoCytomation, Dublin, murine IL-1a were gifts from Prof. S. Martin (Trinity College Dublin, Ireland) flow cytometer was used to analyze fluorescence, and the data Ireland). were analyzed using FlowJo software (Tree Star, Ashland, OR). Cell culture Quantitative PCR C57BL/6 mice were obtained from Harlan Olac (Bicester, U.K.) and were Mouse BMDC were stimulated for 4 h with 3-MA (2.5–10 mM) in the used at 8–16 wk of age. Animals were maintained according to the reg- presence or absence of LPS (10 ng/ml). RNA was purified with the TRIzol ulations of the European Union and the Irish Department of Health. Bone (Invitrogen)/chloroform method; this process was followed by tran- marrow-derived DC (BMDC) were generated as previously described (27) scription into cDNA with a High-Capacity cDNA Reverse Transcription Kit and grown in RPMI 1640 medium (Biosera, East Sussex, U.K.) with 10% (Applied Biosystems). Real-time PCR for the detection of IL-23p19 (il23a) FCS, L-glutamine (2 mM), and penicillin and streptomycin (50 U/ml (Mm00518984_m1) and IL-1b (il1b) (Mm00434228_m1) mRNA was and 50 mg/ml, respectively) (complete medium). The medium was sup- performed with predesigned TaqMan gene expression assays (Applied plemented with GM-CSF (40 ng/ml). Cells were plated out on day 10 Biosystems) using a 7500 Fast Real-Time PCR machine (Applied Bio- and stimulated on day 11. BMDC from TRIF+/+ and TRIF2/2 mice were systems). Expression was normalized to 18s rRNA. provided by Prof. K. Fitzgerald (University of Massachusetts Medical Center, Worcester, MA). Confocal microscopy + CD3+ T cell isolation and culture Immortalized GFP-LC3 iBMM were grown and stimulated on nitric acid- treated glass coverslips (19 mm diameter) in 12-well plates. Cells were CD3+ T cells were purified from spleens of C57BL/6 mice using magnetic fixed with 2% paraformaldehyde for 30 min at room temperature and beads for negative selection (Pan T Cell Isolation Kit II, mouse; Miltenyi permeabilized for 10 min with Triton X-100 (0.1% in PBS).
Load more

Recommended publications
  • Interleukin (IL)-12 and IL-23 and Their Conflicting Roles in Cancer
    Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Interleukin (IL)-12 and IL-23 and Their Conflicting Roles in Cancer Juming Yan,1,2 Mark J. Smyth,2,3 and Michele W.L. Teng1,2 1Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Queensland, Australia 2School of Medicine, University of Queensland, Herston 4006, Queensland, Australia 3Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston 4006, Queensland, Australia Correspondence: [email protected] The balance of proinflammatory cytokines interleukin (IL)-12 and IL-23 plays a key role in shaping the development of antitumor or protumor immunity. In this review, we discuss the role IL-12 and IL-23 plays in tumor biology from preclinical and clinical data. In particular, we discuss the mechanism by which IL-23 promotes tumor growth and metastases and how the IL-12/IL-23 axis of inflammation can be targeted for cancer therapy. he recognized interleukin (IL)-12 cytokine composition whereby the a-subunit (p19, Tfamily currently consists of IL-12, IL-23, p28, p35) and b-subunit (p40, Ebi3) are differ- IL-27, and IL-35 and these cytokines play im- entially shared to generate IL-12 (p40-p35), IL- portant roles in the development of appropriate 23 (p40-p19), IL-27 (Ebi3-p28), and IL-35 immune responses in various disease conditions (p40-p35) (Fig. 1A). Given their ability to share (Vignali and Kuchroo 2012). They act as a link a- and b-subunits, it has been predicted that between the innate and adaptive immune system combinations such as Ebi3-p19 and p28-p40 through mediating the appropriate differentia- could exist and serve physiological function tion of naı¨ve CD4þ T cells into various T helper (Fig.
    [Show full text]
  • Autophagy Suppresses Ras-Driven Epithelial Tumourigenesis by Limiting the Accumulation of Reactive Oxygen Species
    OPEN Oncogene (2017) 36, 5576–5592 www.nature.com/onc ORIGINAL ARTICLE Autophagy suppresses Ras-driven epithelial tumourigenesis by limiting the accumulation of reactive oxygen species This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue. J Manent1,2,3,4,5,12, S Banerjee2,3,4,5, R de Matos Simoes6, T Zoranovic7,13, C Mitsiades6, JM Penninger7, KJ Simpson4,5, PO Humbert3,5,8,9,10 and HE Richardson1,2,5,8,11 Activation of Ras signalling occurs in ~ 30% of human cancers; however, activated Ras alone is not sufficient for tumourigenesis. In a screen for tumour suppressors that cooperate with oncogenic Ras (RasV12)inDrosophila, we identified genes involved in the autophagy pathway. Bioinformatic analysis of human tumours revealed that several core autophagy genes, including GABARAP, correlate with oncogenic KRAS mutations and poor prognosis in human pancreatic cancer, supporting a potential tumour- suppressive effect of the pathway in Ras-driven human cancers. In Drosophila, we demonstrate that blocking autophagy at any step of the pathway enhances RasV12-driven epithelial tissue overgrowth via the accumulation of reactive oxygen species and activation of the Jun kinase stress response pathway. Blocking autophagy in RasV12 clones also results in non-cell-autonomous effects with autophagy, cell proliferation and caspase activation induced in adjacent wild-type cells. Our study has implications for understanding the interplay between perturbations in Ras signalling and autophagy in tumourigenesis,
    [Show full text]
  • The Association of ATG16L1 Variations with Clinical Phenotypes of Adult-Onset Still’S Disease
    G C A T T A C G G C A T genes Article The Association of ATG16L1 Variations with Clinical Phenotypes of Adult-Onset Still’s Disease Wei-Ting Hung 1,2, Shuen-Iu Hung 3 , Yi-Ming Chen 4,5,6 , Chia-Wei Hsieh 6,7, Hsin-Hua Chen 6,7,8 , Kuo-Tung Tang 5,6,7 , Der-Yuan Chen 9,10,11,* and Tsuo-Hung Lan 1,5,12,13,* 1 Institute of Clinical Medicine, National Yang-Ming Chiao Tung University, Taipei 11221, Taiwan; [email protected] 2 Department of Medical Education, Taichung Veterans General Hospital, Taichung 40705, Taiwan 3 Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Linkou, Taoyuan 33305, Taiwan; [email protected] 4 Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan; [email protected] 5 School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; [email protected] 6 Rong Hsing Research Center for Translational Medicine & Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 40227, Taiwan; [email protected] (C.-W.H.); [email protected] (H.-H.C.) 7 Division of Allergy, Immunology, and Rheumatology, Taichung Veterans General Hospital, Taichung 40705, Taiwan 8 Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung 40705, Taiwan 9 Translational Medicine Laboratory, Rheumatology and Immunology Center, China Medical University Hospital, Taichung 40447, Taiwan 10 Rheumatology and Immunology Center, China Medical University Hospital, Taichung 40447, Taiwan Citation: Hung, W.-T.; Hung, S.-I.; 11 School of Medicine, China Medical University, Taichung 40447, Taiwan Chen, Y.-M.; Hsieh, C.-W.; Chen, 12 Tsao-Tun Psychiatric Center, Ministry of Health and Welfare, Nantou 54249, Taiwan H.-H.; Tang, K.-T.; Chen, D.-Y.; Lan, 13 Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli 35053, Taiwan T.-H.
    [Show full text]
  • Astrocyte-Specific Expression of Interleukin 23 Leads to An
    Nitsch et al. Journal of Neuroinflammation (2021) 18:101 https://doi.org/10.1186/s12974-021-02140-z RESEARCH Open Access Astrocyte-specific expression of interleukin 23 leads to an aggravated phenotype and enhanced inflammatory response with B cell accumulation in the EAE model Louisa Nitsch1*†, Simon Petzinna1†, Julian Zimmermann1, Linda Schneider1,2, Marius Krauthausen1, Michael T. Heneka3, Daniel R. Getts4, Albert Becker5 and Marcus Müller1,6 Abstract Background: Interleukin 23 is a critical cytokine in the pathogenesis of multiple sclerosis. But the local impact of interleukin 23 on the course of neuroinflammation is still not well defined. To further characterize the effect of interleukin 23 on CNS inflammation, we recently described a transgenic mouse model with astrocyte-specific expression of interleukin 23 (GF-IL23 mice). The GF-IL23 mice spontaneously develop a progressive ataxic phenotype with cerebellar tissue destruction and inflammatory infiltrates with high amounts of B cells most prominent in the subarachnoid and perivascular space. Methods: To further elucidate the local impact of the CNS-specific interleukin 23 synthesis in autoimmune neuroinflammation, we induced a MOG35-55 experimental autoimmune encephalomyelitis (EAE) in GF-IL23 mice and WT mice and analyzed the mice by histology, flow cytometry, and transcriptome analysis. Results: We were able to demonstrate that local interleukin 23 production in the CNS leads to aggravation and chronification of the EAE course with a severe paraparesis and an ataxic phenotype. Moreover, enhanced multilocular neuroinflammation was present not only in the spinal cord, but also in the forebrain, brainstem, and predominantly in the cerebellum accompanied by persisting demyelination. Thereby, interleukin 23 creates a pronounced proinflammatory response with accumulation of leukocytes, in particular B cells, CD4+ cells, but also γδ T cells and activated microglia/macrophages.
    [Show full text]
  • The Role of IL-12/23 in T–Cell Related Chronic Inflammation; Implications of Immunodeficiency and Therapeutic Blockade
    The role of IL-12/23 in T–cell related chronic inflammation; implications of immunodeficiency and therapeutic blockade Authors: Anna Schurich, PhD1, Charles Raine, MRCP2, Vanessa Morris, MD, FRCP2 and Coziana Ciurtin, PhD, FRCP2 1. Division of Infection and Immunity, University College London, London 2. Department of Rheumatology, University College London Hospitals NHS Trust, London Corresponding authors: Dr. Coziana Ciurtin, Department of Rheumatology, University College London Hospitals NHS Trust, 3rd Floor Central, 250 Euston Road, London, NW1 2PG, email: [email protected]. Short title: The role of IL-12/23 in chronic inflammation The authors declare no conflicts of interest Abstract In this review, we discuss the divergent role of the two closely related cytokine, interleukin (IL)-12 and IL-23, in shaping immune responses. In light of current therapeutic developments using biologic agents to block these two pathways, a better understanding of the immunological function of these cytokines is pivotal. Introduction: The cytokines IL-12/23 are known to be pro-inflammatory and recognised to be involved in driving autoimmunity and inflammation. Antibodies blocking IL-12/23 have now been developed to treat patients with chronic inflammatory conditions such as seronegative spondyloarthropathy, psoriasis, inflammatory bowel disease, as well as multiple sclerosis. The anti-IL-12/23 drugs are very exciting for the clinician to study and use in these patient groups who have chronic, sometimes disabling conditions - either as a first line, or when other biologics such as anti-TNF therapies have failed. However, IL-12/23 have important biological functions, and it is recognised that their presence drives the body’s response to bacterial and viral infections, as well as tumour control via their regulation of T cell function.
    [Show full text]
  • IL-1Β and IL-23 Promote Extrathymic Commitment of CD27+CD122
    IL-1β and IL-23 Promote Extrathymic Commitment of CD27 +CD122− δγ T Cells to δγ T17 Cells This information is current as Andreas Muschaweckh, Franziska Petermann and Thomas of September 27, 2021. Korn J Immunol published online 30 August 2017 http://www.jimmunol.org/content/early/2017/08/30/jimmun ol.1700287 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/08/30/jimmunol.170028 Material 7.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 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 Author Choice Freely available online through The Journal of Immunology Author Choice option 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 August 30, 2017, doi:10.4049/jimmunol.1700287 The Journal of Immunology IL-1b and IL-23 Promote Extrathymic Commitment of CD27+CD1222 gd T Cells to gdT17 Cells Andreas Muschaweckh,*,1 Franziska Petermann,*,1,2 and Thomas Korn*,† gdT17 cells are a subset of gd T cells committed to IL-17 production and are characterized by the expression of IL-23R and CCR6 and lack of CD27 expression.
    [Show full text]
  • RT² Profiler PCR Array (96-Well Format and 384-Well [4 X 96] Format)
    RT² Profiler PCR Array (96-Well Format and 384-Well [4 x 96] Format) Mouse Common Cytokines Cat. no. 330231 PAMM-021ZA For pathway expression analysis Format For use with the following real-time cyclers RT² Profiler PCR Array, Applied Biosystems® models 5700, 7000, 7300, 7500, Format A 7700, 7900HT, ViiA™ 7 (96-well block); Bio-Rad® models iCycler®, iQ™5, MyiQ™, MyiQ2; Bio-Rad/MJ Research Chromo4™; Eppendorf® Mastercycler® ep realplex models 2, 2s, 4, 4s; Stratagene® models Mx3005P®, Mx3000P®; Takara TP-800 RT² Profiler PCR Array, Applied Biosystems models 7500 (Fast block), 7900HT (Fast Format C block), StepOnePlus™, ViiA 7 (Fast block) RT² Profiler PCR Array, Bio-Rad CFX96™; Bio-Rad/MJ Research models DNA Format D Engine Opticon®, DNA Engine Opticon 2; Stratagene Mx4000® RT² Profiler PCR Array, Applied Biosystems models 7900HT (384-well block), ViiA 7 Format E (384-well block); Bio-Rad CFX384™ RT² Profiler PCR Array, Roche® LightCycler® 480 (96-well block) Format F RT² Profiler PCR Array, Roche LightCycler 480 (384-well block) Format G RT² Profiler PCR Array, Fluidigm® BioMark™ Format H Sample & Assay Technologies Description The Mouse Common Cytokines RT² Profiler PCR Array profiles the expression of 84 important cytokine genes. This array includes interferons and interleukins as well as the bone morphogenetic proteins (BMP) and members of the TGF-ß family. Also represented are platelet-derived and vascular endothelial growth factors. Tumor necrosis factors are included as well as other cytokine-related genes. Using real-time PCR, you can easily and reliably analyze expression of a focused panel of genes related to cytokines with this array.
    [Show full text]
  • The ATG5-Binding and Coiled Coil Domains of ATG16L1 Maintain
    AUTOPHAGY 2019, VOL. 15, NO. 4, 599–612 https://doi.org/10.1080/15548627.2018.1534507 RESEARCH PAPER The ATG5-binding and coiled coil domains of ATG16L1 maintain autophagy and tissue homeostasis in mice independently of the WD domain required for LC3-associated phagocytosis Shashank Raia*, Maryam Arasteha*, Matthew Jeffersona*, Timothy Pearsona, Yingxue Wanga, Weijiao Zhanga, Bertalan Bicsaka, Devina Divekara, Penny P. Powella, Ronald Naumannb, Naiara Berazac, Simon R. Cardingc, Oliver Floreyd, Ulrike Mayer e, and Thomas Wilemana,c aNorwich Medical School, University of East Anglia, Norwich, Norfolk, UK; bMax-Planck-Institute of Molecular Cell Biology and Genetics, Dresden, Germany; cQuadram Institute Bioscience, Norwich, Norfolk, UK; dSignalling Programme, Babraham Institute, Cambridge, UK; eSchool of Biological Sciences, University of East Anglia, Norwich, Norfolk, UK ABSTRACT ARTICLE HISTORY Macroautophagy/autophagy delivers damaged proteins and organelles to lysosomes for degradation, Received 8 February 2018 and plays important roles in maintaining tissue homeostasis by reducing tissue damage. The transloca- Revised 28 September 2018 tion of LC3 to the limiting membrane of the phagophore, the precursor to the autophagosome, during Accepted 5 October 2018 autophagy provides a binding site for autophagy cargoes, and facilitates fusion with lysosomes. An KEYWORDS autophagy-related pathway called LC3-associated phagocytosis (LAP) targets LC3 to phagosome and ATG16L1; brain; endosome membranes during uptake of bacterial and fungal pathogens, and targets LC3 to swollen LC3-associated endosomes containing particulate material or apoptotic cells. We have investigated the roles played by phagocytosis; sequestosome autophagy and LAP in vivo by exploiting the observation that the WD domain of ATG16L1 is required for 1/p62 inclusions; tissue LAP, but not autophagy.
    [Show full text]
  • Expression of Interleukin-23 and Its Receptors in Human Squamous Cell Carcinoma of the Oral Cavity
    MOLECULAR MEDICINE REPORTS 3: 89-93, 2010 89 Expression of interleukin-23 and its receptors in human squamous cell carcinoma of the oral cavity MASAKATSU FUKUDA, MASAHIRO EHARA, SEIJI SUZUKI and HIDEAKI SAKASHITA Second Division of Oral and Maxillofacial Surgery, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, Saitama 350-0283, Japan Received June 30, 2009; Accepted September 18, 2009 DOI: 10.3892/mmr_00000223 Abstract. Interleukin (IL)-23 is a heterodimeric cytokine inflammatory drugs reduces the incidence of a variety of comprising IL-12p40 and the recently cloned IL-23-specific human tumors (3). Although the blockade of certain of these p19 subunit. Like IL-12, IL-23 is expressed predominantly mediators has been shown to be efficacious in experimental by activated dendritic cells and phagocytic cells. Both settings, it is still unclear whether the inflammatory reaction at cytokines induce interferon-γ secretion by T cells, and the tumor site promotes tumor growth or simply indicates the antagonistically regulate local inflammatory responses in the failed attempt of the immune system to eliminate the rising tumor microenvironment as well as the infiltration of intra- malignancy. Cytokines comprise a large family of secreted epithelial lymphocytes. Although the expression of IL-23 in proteins that bind to and signal through defined cell surface various organs has been reported, it is unclear whether IL-23 receptors on a wide variety of target cells, thus playing a is expressed in oral cancer. The expression of IL-23 and its pivotal role in the establishment and maintenance of homeo- receptors was examined in human oral squamous cell carci- stasis.
    [Show full text]
  • Intensifies Interleukin-23-Driven Pathogenicity of T Helper Cells In
    cells Article Interferon-β Intensifies Interleukin-23-Driven Pathogenicity of T Helper Cells in Neuroinflammatory Disease Agnieshka Agasing, James L. Quinn, Gaurav Kumar and Robert C. Axtell * Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; [email protected] (A.A.); [email protected] (J.L.Q.); [email protected] (G.K.) * Correspondence: [email protected]; Tel.: +1-(405)-271-2354 Abstract: Interferon (IFN)-β is a popular therapy for multiple sclerosis (MS). However, 25–40% of patients are nonresponsive to this therapy, and it worsens neuromyelitis optica (NMO), another neuroinflammatory disease. We previously identified, in both NMO patients and in mice, that IFN-β treatment had inflammatory effects in T Helper (TH) 17-induced disease through the production of the inflammatory cytokine IL-6. However, other studies have shown that IFN-β inhibits the differentiation and function of TH17 cells. In this manuscript, we identified that IFN-β had differential effects on discrete stages of TH17 development. During early TH17 development, IFN-β inhibits IL-17 production. Conversely, during late TH17 differentiation, IFN-β synergizes with IL-23 to promote a pathogenic T cell that has both TH1 and TH17 characteristics and expresses elevated levels of the potent inflammatory cytokines IL-6 and GM-CSF and the transcription factor BLIMP. Together, these findings help resolve a paradox surrounding IFN-β and TH17-induced disease and illuminate the pathways responsible for the pathophysiology of NMO and MS patients who are IFN-β nonresponders. Citation: Agasing, A.; Quinn, J.L.; Kumar, G.; Axtell, R.C.
    [Show full text]
  • The Bacterial Peptidoglycan-Sensing Molecules NOD1 and NOD2 Promote CD8 + Thymocyte Selection
    The Bacterial Peptidoglycan-Sensing Molecules NOD1 and NOD2 Promote CD8 + Thymocyte Selection This information is current as Marianne M. Martinic, Irina Caminschi, Meredith O'Keeffe, of September 24, 2021. Therese C. Thinnes, Raelene Grumont, Steve Gerondakis, Dianne B. McKay, David Nemazee and Amanda L. Gavin J Immunol published online 15 February 2017 http://www.jimmunol.org/content/early/2017/02/15/jimmun ol.1601462 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/02/15/jimmunol.160146 Material 2.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 24, 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 © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published February 15, 2017, doi:10.4049/jimmunol.1601462 The Journal of Immunology The Bacterial Peptidoglycan-Sensing Molecules NOD1 and NOD2 Promote CD8+ Thymocyte Selection Marianne M. Martinic,*,1 Irina Caminschi,†,‡,2 Meredith O’Keeffe,†,2 Therese C. Thinnes,* Raelene Grumont,†,2 Steve Gerondakis,†,2 Dianne B.
    [Show full text]
  • ATG16L1 Gene Autophagy Related 16 Like 1
    ATG16L1 gene autophagy related 16 like 1 Normal Function The ATG16L1 gene provides instructions for making a protein that is required for a process called autophagy. Cells use this process to recycle worn-out cell parts and break down certain proteins when they are no longer needed. Autophagy also plays an important role in controlled cell death (apoptosis). Additionally, autophagy is involved in the body's inflammatory response and helps the immune system destroy some types of harmful bacteria and viruses. Health Conditions Related to Genetic Changes Crohn disease At least one variation in the ATG16L1 gene is associated with an increased risk of Crohn disease, particularly a form of the disorder that affects the lower part of the small intestine (the ileum) and the colon. This increased risk has been found primarily in people of northern European ancestry. The identified ATG16L1 variation changes a single protein building block (amino acid) in a critical region of the ATG16L1 protein. Specifically, it replaces the amino acid threonine with the amino acid alanine at protein position 300 (written as Thr300Ala or T300A). This change in the ATG16L1 gene impairs the autophagy process, allowing worn-out cell parts and harmful bacteria to persist when they would otherwise be destroyed. These cell components and bacteria may trigger an inappropriate immune system response, leading to chronic inflammation in the intestinal walls and the digestive problems characteristic of Crohn disease. Researchers continue to study the relationship between changes in the ATG16L1 gene and a person's risk of developing this disorder. Other Names for This Gene • APG16 autophagy 16-like • APG16L • ATG16 autophagy related 16-like 1 (S.
    [Show full text]