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  • Phagocytosis‐dependent activation of a TLR9–BTK–calcineurin–NFAT pathway co‐ordinates innate immunity to Aspergillus fumigatus
    1. Susanne Herbst1,
    2. Anand Shah1,
    3. Maria Mazon Moya2,
    4. Vanessa Marzola1,
    5. Barbara Jensen1,
    6. Anna Reed3,
    7. Mark A Birrell4,
    8. Shinobu Saijo5,
    9. Serge Mostowy2,
    10. Sunil Shaunak1 and
    11. Darius Armstrong‐James*,1,4
    1. 1Department of Infectious Diseases and Immunity, Imperial College London, London, UK
    2. 2MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK
    3. 3Lung Transplant Unit, Royal Brompton and Harefield Hospital, London, UK
    4. 4National Heart and Lung Institute, Imperial College London, London, UK
    5. 5Medical Mycology Research Centre, Chiba University, Chiba, Japan
    1. *Corresponding author. Tel: +44 207 594 3187; E‐mail: d.armstrong{at}imperial.ac.uk

    Whilst calcineurin inhibition is common during organ transplantation, it also increases susceptibility to life‐threatening invasive pulmonary aspergillosis. Calcineurin is found here to mediate phagocytosis‐dependent innate immune responses to Aspergillus fumigatus in macrophages.

    Synopsis

    Whilst calcineurin inhibition is common during organ transplantation, it also increases susceptibility to life‐threatening invasive pulmonary aspergillosis. Calcineurin is found here to mediate phagocytosis‐dependent innate immune responses to Aspergillus fumigatus in macrophages.

    • Phagocytosis‐dependent activation of TLR9 by the human mould pathogen A. fumigatus drives calcineurin–NFAT transcriptional responses in macrophages.

    • Activation of calcineurin–NFAT by TLR9 is independent of MyD88 and Dectin‐1–spleen tyrosine kinase, but dependent on Bruton's tyrosine kinase.

    • This pathway is critical for macrophage TNF‐α production and subsequent chemotaxis of neutrophil to the airway during pulmonary aspergillosis.

    • Direct inhibition of the TLR9–BTK–calcineurin–NFAT pathway by calcineurin inhibitors is a key mechanism that increases clinical susceptibility to pulmonary aspergillosis.

    • aspergillus
    • calcineurin
    • phagocytosis
    • TLR9
    • Transplant
    • Received August 18, 2014.
    • Revision received December 29, 2014.
    • Accepted January 8, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Susanne Herbst, Anand Shah, Maria Mazon Moya, Vanessa Marzola, Barbara Jensen, Anna Reed, Mark A Birrell, Shinobu Saijo, Serge Mostowy, Sunil Shaunak, Darius Armstrong‐James
  • Alzheimer‐associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation
    1. Julia R Clarke1,2,,
    2. Natalia M Lyra e Silva1,,
    3. Claudia P Figueiredo2,
    4. Rudimar L Frozza1,
    5. Jose H Ledo1,
    6. Danielle Beckman1,
    7. Carlos K Katashima3,
    8. Daniela Razolli3,
    9. Bruno M Carvalho3,
    10. Renata Frazão4,
    11. Marina A Silveira4,
    12. Felipe C Ribeiro1,
    13. Theresa R Bomfim1,
    14. Fernanda S Neves2,
    15. William L Klein5,
    16. Rodrigo Medeiros6,
    17. Frank M LaFerla6,
    18. Jose B Carvalheira3,
    19. Mario J Saad3,
    20. Douglas P Munoz7,
    21. Licio A Velloso3,
    22. Sergio T Ferreira1,8 and
    23. Fernanda G De Felice*,1
    1. 1Institute of Medical Biochemistry Leopoldo de Meis Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
    2. 2School of Pharmacy Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
    3. 3Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil
    4. 4Department of Anatomy, Institute of Biomedical Sciences University of São Paulo, SP, Brazil
    5. 5Department of Neurobiology, Northwestern University, Evanston, IL, USA
    6. 6Institute for Memory Impairments and Neurological Disorders University of California, Irvine, CA, USA
    7. 7Center for Neuroscience Studies, Queen's University, Kingston, ON, Canada
    8. 8Institute of Biophysics Carlos Chagas Filho Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
    1. *Corresponding author. Tel: +55 21 38888308; E‐mail: felice{at}bioqmed.ufrj.br
    1. These authors contributed equally to this work

    Centrally administered Aβ oligomers can trigger insulin resistance by engaging ER stress and inflammatory signals in the central nervous system. This study provides important insights into the link between Alzheimer's disease and diabetes by pointing to a common etiology.

    Synopsis

    Centrally administered Aβ oligomers can trigger insulin resistance by engaging ER stress and inflammatory signals in the central nervous system. This study provides important insights into the link between Alzheimer's disease and diabetes by pointing to a common etiology.

    • Aβ oligomers (ΑβOs), toxins that accumulate in the AD brain and have been linked to neuronal dysfunction in brain areas related to learning and memory, impact the hypothalamus of mice and macaques, revealing a novel toxic mechanism of AβOs in the brain.

    • Infusion of AβOs in the brain triggers peripheral glucose intolerance, insulin resistance and other diabetes‐related metabolic alterations in mice. Similar metabolic alterations were verified in two transgenic mouse models of AD.

    • Blockade of brain inflammation or ER stress attenuates peripheral glucose intolerance induced by brain infusion of AβOs, suggesting that AβOs use a central route to disrupt metabolic control in peripheral tissues.

    • Current results may explain why AD patients have increased risk of developing diabetes, and suggest that targeting the hypothalamus may constitute an approach to combat peripheral metabolic deregulation in AD.

    • Alzheimer's disease
    • ER stress
    • hypothalamus
    • inflammation
    • insulin resistance
    • Received April 30, 2014.
    • Revision received December 12, 2014.
    • Accepted December 17, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Julia R Clarke, Natalia M Lyra e Silva, Claudia P Figueiredo, Rudimar L Frozza, Jose H Ledo, Danielle Beckman, Carlos K Katashima, Daniela Razolli, Bruno M Carvalho, Renata Frazão, Marina A Silveira, Felipe C Ribeiro, Theresa R Bomfim, Fernanda S Neves, William L Klein, Rodrigo Medeiros, Frank M LaFerla, Jose B Carvalheira, Mario J Saad, Douglas P Munoz, Licio A Velloso, Sergio T Ferreira, Fernanda G De Felice
  • FAT FLUX: enzymes, regulators, and pathophysiology of intracellular lipolysis
    1. Rudolf Zechner (rudolf.zechner{at}uni-graz.at) 1
    1. 1Institute of Molecular Biosciences, University of Graz, Graz, Austria

    The great 19th century French physiologist Claude Bernard reasoned “Man can learn nothing except by going from the known to the unknown”. This premise is particularly applicable to the progression of discoveries made in the field of fat metabolism since Bernard's time. Beginning with his groundbreaking discovery of fat digestion (later termed “lipolysis”) in 1848, research addressing the basic processes of cellular storage and mobilization of fat has steadily advanced. Even after 150 years of research dedicated to lipolysis, exciting new principles have continued to emerge in the last 10 years. This Perspective summarizes these recent landmark discoveries in the field and emphasizes their relevance for the pathogenesis of extremely prevalent diseases such as obesity, heart disease, and cancer.

    The 2015 Louis–Jeantet Prize for Medicine winner Rudolf Zechner offers his personal account of the history and current state of the art of research in the pathophysiology of intracellular lipolysis and its implications for disease.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Rudolf Zechner
  • Apolipoprotein E promotes subretinal mononuclear phagocyte survival and chronic inflammation in age‐related macular degeneration
    1. Olivier Levy1,2,3,,
    2. Bertrand Calippe1,2,3,,
    3. Sophie Lavalette1,2,3,
    4. Shulong J Hu1,2,3,
    5. William Raoul1,2,3,
    6. Elisa Dominguez1,2,3,
    7. Michael Housset1,2,3,
    8. Michel Paques1,2,3,
    9. José‐Alain Sahel1,2,3,
    10. Alexis‐Pierre Bemelmans1,2,3,4,5,
    11. Christophe Combadiere6,7,8,
    12. Xavier Guillonneau1,2,3 and
    13. Florian Sennlaub*,1,2,3
    1. 1INSERM, Paris, France
    2. 2UPMC Univ Paris 06 UMR_S 968 Institut de la Vision, Paris, France
    3. 3Centre Hospitalier National d'Ophtalmologie des Quinze‐Vingts INSERM‐DHOS CIC 503, Paris, France
    4. 4CEA DSV I²BM Molecular Imaging Research Center (MIRCen), Fontenay‐aux‐Roses, France
    5. 5CNRS CEA URA 2210, Fontenay‐aux‐Roses, France
    6. 6Sorbonne Universités, UPMC Univ Paris 06 CR7 Centre d'Immunologie et des Maladies Infectieuses (CIMI‐Paris), Paris, France
    7. 7INSERM U1135 CIMI‐Paris, Paris, France
    8. 8CNRS ERL 8255 CIMI‐Paris, Paris, France
    1. *Corresponding author. Tel: +33 1 53 46 26 93; E‐mail: florian.sennlaub{at}inserm.fr
    1. These authors contributed equally to this work

    In age‐related macular degeneration, subretinal mononuclear phagocytes (MP) express high APOE levels, which prolongs their survival and accumulation by inducing IL‐6, which in turn promotes chronic subretinal inflammation.

    Synopsis

    In age‐related macular degeneration, subretinal mononuclear phagocytes (MP) express high APOE levels, which prolongs their survival and accumulation by inducing IL‐6, which in turn promotes chronic subretinal inflammation.

    • Pathogenic subretinal mononuclear phagocytes, observed in age‐related macular degeneration in human donor tissue and in the Cx3cr1−/− mouse model of subretinal inflammation, express high levels of APOE.

    • High levels of APOE activate the TLR2‐CD14‐dependent innate immunity receptor cluster and induce IL‐6 in mononuclear phagocytes.

    • IL‐6 inhibits FASL expression in the retinal pigment epithelium and increases subretinal mononuclear phagocyte survival.

    • ApoE deletion and pharmacological IL‐6 inhibition prevents pathogenic age‐ and stress‐induced subretinal MP accumulation in Cx3cr1−/−mice.

    • age‐related macular degeneration
    • apolipoprotein E
    • interleukin 6
    • mononuclear phagocyte
    • neuroinflammation
    • Received August 8, 2014.
    • Revision received December 11, 2014.
    • Accepted December 15, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Olivier Levy, Bertrand Calippe, Sophie Lavalette, Shulong J Hu, William Raoul, Elisa Dominguez, Michael Housset, Michel Paques, José‐Alain Sahel, Alexis‐Pierre Bemelmans, Christophe Combadiere, Xavier Guillonneau, Florian Sennlaub
  • An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease
    1. Yasuhiko Kizuka1,
    2. Shinobu Kitazume*,1,
    3. Reiko Fujinawa1,
    4. Takashi Saito2,
    5. Nobuhisa Iwata2,3,
    6. Takaomi C Saido2,
    7. Miyako Nakano4,
    8. Yoshiki Yamaguchi5,
    9. Yasuhiro Hashimoto6,
    10. Matthias Staufenbiel7,
    11. Hiroyuki Hatsuta8,
    12. Shigeo Murayama8,
    13. Hiroshi Manya9,
    14. Tamao Endo9 and
    15. Naoyuki Taniguchi*,1
    1. 1Disease Glycomics Team, RIKEN‐Max Planck Joint Research Center Global Research Cluster RIKEN, Wako, Japan
    2. 2Laboratory for Proteolytic Neuroscience RIKEN Brain Science Institute, Wako, Japan
    3. 3Department of Genome‐based Drug Discovery, Unit of Molecular Medicinal Sciences, Graduate School of Biomedical Sciences Nagasaki University, Nagasaki, Japan
    4. 4Graduate School of Advanced Sciences of Matter Hiroshima University, Higashihiroshima Hiroshima, Japan
    5. 5Structural Glycobiology Team, RIKEN‐Max Planck Joint Research Center Global Research Cluster RIKEN, Wako, Japan
    6. 6Department of Biochemistry, Fukushima Medical University School of Medicine, Fukushima, Japan
    7. 7Novartis Institutes for Biomedical Research, Basel, Switzerland
    8. 8Department of Neuropathology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi‐ku Tokyo, Japan
    9. 9Molecular Glycobiology, Research Team for Mechanism of Aging, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi‐ku Tokyo, Japan
    1. * Corresponding author. Tel: +81 48 467 9616; Fax: +81 48 467 9617; E‐mail: shinobuk{at}riken.jp

      Corresponding author. Tel: +81 48 467 9616; Fax: +81 48 467 9617; E‐mail: dglycotani{at}riken.jp

    Bisecting GlcNAc modification of BACE1 by GnT‐III is a novel regulator of BACE1 stability. Loss of GnT‐III curbs BACE1‐mediated Aβ plaque generation. Hence, the bisecting GlcNAc biosynthesis pathway is a promising new target for AD therapy.

    Synopsis

    Bisecting GlcNAc modification of BACE1 by GnT‐III is a novel regulator of BACE1 stability. Loss of GnT‐III curbs BACE1‐mediated Aβ plaque generation. Hence, the bisecting GlcNAc biosynthesis pathway is a promising new target for AD therapy.

    • Alzheimer's disease (AD) patients present high levels of bisecting GlcNAc modifications on BACE1.

    • Loss of bisecting GlcNAc reduces BACE1‐mediated Aβ generation, leading to amelioration of AD pathology.

    • Loss of bisecting GlcNAc reduces BACE1–APP localization.

    • The enzyme responsible for the biosynthesis of bisecting GlcNAc, GnT‐III, is therefore a potential new drug target for AD.

    • Alzheimer's disease
    • amyloid‐β
    • BACE1
    • bisecting GlcNAc
    • GnT‐III
    • Received August 4, 2014.
    • Revision received December 2, 2014.
    • Accepted December 12, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Yasuhiko Kizuka, Shinobu Kitazume, Reiko Fujinawa, Takashi Saito, Nobuhisa Iwata, Takaomi C Saido, Miyako Nakano, Yoshiki Yamaguchi, Yasuhiro Hashimoto, Matthias Staufenbiel, Hiroyuki Hatsuta, Shigeo Murayama, Hiroshi Manya, Tamao Endo, Naoyuki Taniguchi
  • Impairment of chaperone‐mediated autophagy leads to selective lysosomal degradation defects in the lysosomal storage disease cystinosis
    1. Gennaro Napolitano1,
    2. Jennifer L Johnson1,
    3. Jing He1,
    4. Celine J Rocca2,
    5. Jlenia Monfregola1,
    6. Kersi Pestonjamasp3,
    7. Stephanie Cherqui2 and
    8. Sergio D Catz*,1
    1. 1Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
    2. 2Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
    3. 3Cancer Center Microscopy Shared Resource, University of California San Diego, La Jolla, CA, USA
    1. *Corresponding author. Tel: +1 858 784 7932; Fax: +1 858 784 2054; E‐mail: scatz{at}scripps.edu

    Impaired chaperone‐mediated autophagy (CMA) due to aberrant CMA receptor LAMP2A expression and localization is shown to be an important pathogenic factor in cystinosis, a lysosomal storage disorder due to defects in the cystine transporter cystinosin.

    Synopsis

    Impaired chaperone‐mediated autophagy (CMA) due to aberrant CMA receptor LAMP2A expression and localization is shown to be an important pathogenic factor in cystinosis, a lysosomal storage disorder due to defects in the cystine transporter cystinosin.

    • LAMP2A downregulation and impaired CMA were identified in cystinosis.

    • LC3B levels are increased but macroautophagic flux and mTOR activity are not impaired in cystinosis.

    • CMA was not corrected by reduction of lysosomal metabolite accumulation thus highlighting a lysosomal overload‐independent defect in cystinosis.

    • autophagy
    • CTNS
    • cystinosis
    • lysosomal storage disorder
    • lysosomal trafficking
    • Received May 6, 2014.
    • Revision received December 7, 2014.
    • Accepted December 9, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Gennaro Napolitano, Jennifer L Johnson, Jing He, Celine J Rocca, Jlenia Monfregola, Kersi Pestonjamasp, Stephanie Cherqui, Sergio D Catz
  • Functional drug screening reveals anticonvulsants as enhancers of mTOR‐independent autophagic killing of Mycobacterium tuberculosis through inositol depletion
    1. Mark Schiebler1,,
    2. Karen Brown1,2,,
    3. Krisztina Hegyi1,,,
    4. Sandra M Newton3,,
    5. Maurizio Renna4,,
    6. Lucy Hepburn1,
    7. Catherine Klapholz1,
    8. Sarah Coulter1,
    9. Andres Obregón‐Henao5,
    10. Marcela Henao Tamayo5,
    11. Randall Basaraba5,
    12. Beate Kampmann3,
    13. Katherine M Henry6,
    14. Joseph Burgon6,
    15. Stephen A Renshaw6,
    16. Angeleen Fleming4,
    17. Robert R Kay7,
    18. Karen E Anderson8,
    19. Phillip T Hawkins8,
    20. Diane J Ordway*,5,
    21. David C Rubinsztein*,4 and
    22. Rodrigo Andres Floto*,1,2
    1. 1Department of Medicine, Cambridge Institute for Medical Research University of Cambridge, Cambridge, UK
    2. 2Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge, UK
    3. 3Department of Paediatric Infectious Diseases and Allergy, Imperial College London, London, UK
    4. 4Department of Medical Genetics, Cambridge Institute for Medical Research University of Cambridge, Cambridge, UK
    5. 5Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA
    6. 6Department of Infection and Immunity, University of Sheffield Western Bank, Sheffield, UK
    7. 7MRC Laboratory of Molecular Biology, Cambridge, UK
    8. 8The Inositide Laboratory, Babraham Institute Babraham Research Campus, Cambridge, UK
    1. * Corresponding author. Tel: +44 1223 768801; Fax: +44 1223 762640; E‐mail: arf27{at}cam.ac.uk

      Corresponding author. Tel: +44 1223 762608; Fax: +44 1223 762640; E‐mail: dcr1000{at}cam.ac.uk

      Corresponding author. Tel: + 1 970 491 7840; Fax: +1 970 491 1815; E‐mail: D.Ordway{at}colostate.edu

    1. Contributed equally to this work

    Carbamazepine reveals a novel mechanism of mTOR‐independent control of autophagy that may be manipulated pharmacologically and provides proof of principle that therapeutic autophagy stimulation can be an effective strategy to treat multidrug‐resistant tuberculosis.

    Synopsis

    Carbamazepine reveals a novel mechanism of mTOR‐independent control of autophagy that may be manipulated pharmacologically and provides proof of principle that therapeutic autophagy stimulation can be an effective strategy to treat multidrug‐resistant tuberculosis.

    • Functional screening of FDA‐approved drugs identified two anticonvulsants, carbamazepine and valproic acid, capable of enhancing autophagic killing of mycobacteria from primary human monocyte derived and alveolar macrophages.

    • In vivo, carbamazepine enhanced clearance of M. marinum from zebrafish and multidrug‐resistant M. tuberculosis from mice at drug concentrations achievable in man during therapeutic dosing.

    • Carbamazepine stimulates autophagy by blocking myo‐inositol uptake in macrophages, leading to decreased phosphatidylinositol, inositol trisphosphate, and cellular ATP but activation of AMP kinase.

    • autophagy
    • multidrug‐resistant
    • myo‐inositol
    • tuberculosis
    • Received April 2, 2014.
    • Revision received December 1, 2014.
    • Accepted December 2, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Mark Schiebler, Karen Brown, Krisztina Hegyi, Sandra M Newton, Maurizio Renna, Lucy Hepburn, Catherine Klapholz, Sarah Coulter, Andres Obregón‐Henao, Marcela Henao Tamayo, Randall Basaraba, Beate Kampmann, Katherine M Henry, Joseph Burgon, Stephen A Renshaw, Angeleen Fleming, Robert R Kay, Karen E Anderson, Phillip T Hawkins, Diane J Ordway, David C Rubinsztein, Rodrigo Andres Floto