Advertisement

 

  • Murine Langerin+ dermal dendritic cells prime CD8+ T cells while Langerhans cells induce cross‐tolerance
    1. Vincent Flacher1,24,
    2. Christoph H Tripp1,2,
    3. David G Mairhofer1,
    4. Ralph M Steinman3,
    5. Patrizia Stoitzner*,1,,
    6. Juliana Idoyaga35 and
    7. Nikolaus Romani*,1,2,
    1. 1Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria
    2. 2Oncotyrol Center for Personalized Cancer Medicine, Innsbruck, Austria
    3. 3Laboratory of Cellular Physiology and Immunology and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY, USA
    4. 4Laboratory of Immunopathology and Therapeutic Chemistry/Laboratory of Excellence MEDALIS, CNRS UPR3572 Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France
    5. 5Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
    1. * Corresponding author. Tel: +43 512 504 28559; Fax: +43 512 504 67 28559; E‐mail: nikolaus.romani{at}i-med.ac.at

      Corresponding author. Tel: +43 512 504 23016; Fax: +43 512 504 67 28592; E‐mail: patrizia.stoitzner{at}i-med.ac.at

    1. These authors contributed equally to this work.

    The properties of two murine skin antigen‐presenting dendritic cell (DC) subsets were investigated in vivo. Following adjuvanted OVA‐immunization, functional differences were found between the DC subsets that may bear translational relevance for vaccination in the skin.

    Synopsis

    The properties of two murine skin antigen‐presenting dendritic cell (DC) subsets were investigated in vivo. Following adjuvanted OVA‐immunization, functional differences were found between the DC subsets that may bear translational relevance for vaccination in the skin.

    • Both Langerin+ dermal DCs and epidermal Langerhans cells (LC) can present exogenous antigen to CD8+ T cells.

    • Langerin+ dermal DCs prime long‐lasting cytotoxic responses, while cross‐presentation by LCs negatively influences CD8+ T‐cell priming.

    • Specific adjuvants can be used to independently harness the different potential of distinct DC subsets simultaneously targeted by an antigen.

    • Treatment of skin with imiquimod, an agonist of TLR7, does not result in potent immune responses when the antigen is targeted to Langerin, thereby relativizing the paradigm stating that mature DCs always promote immunity.

    • CD8+ T‐cell responses
    • dendritic cells
    • Langerhans cells
    • skin
    • tolerance
    • Received July 12, 2013.
    • Revision received July 4, 2014.
    • Accepted July 8, 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.

    Vincent Flacher, Christoph H Tripp, David G Mairhofer, Ralph M Steinman, Patrizia Stoitzner, Juliana Idoyaga, Nikolaus Romani
  • Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa
    1. Yael Pewzner‐Jung*,1,
    2. Shaghayegh Tavakoli Tabazavareh2,
    3. Heike Grassmé2,
    4. Katrin Anne Becker2,
    5. Lukasz Japtok3,
    6. Jörg Steinmann4,
    7. Tammar Joseph1,
    8. Stephan Lang5,
    9. Burkhard Tuemmler6,
    10. Edward H Schuchman7,
    11. Alex B Lentsch8,
    12. Burkhard Kleuser3,
    13. Michael J Edwards8,
    14. Anthony H Futerman1 and
    15. Erich Gulbins*,2,8
    1. 1Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel
    2. 2Department of Molecular Biology, University Hospital Essen, University of Duisburg‐Essen, Essen, Germany
    3. 3Department of Nutritional Science, University of Potsdam, Potsdam, Germany
    4. 4Department of Microbiology, University Hospital Essen, University of Duisburg‐Essen, Essen, Germany
    5. 5Department of Otorhinolaryngology, University Hospital Essen, University of Duisburg‐Essen, Essen, Germany
    6. 6Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, Hannover, Germany
    7. 7Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
    8. 8Department of Surgery, University of Cincinnati, Cincinnati, OH, USA
    1. * Corresponding author. Tel: +49 201 723 3118; Fax: 49 201 723 5974; E‐mail: erich.gulbins{at}uni-due.de

      Corresponding author. Tel: +972 8 9343256; Fax: +972 8 9344112; E‐mail: yael.pewzner-jung{at}weizmann.ac.il

    Sphingosine functions as an important anti‐bacterial agent in healthy airways but this defence mechanism is lost in cystic fibrosis. The sensitivity of cystic fibrosis mice to infection can be corrected by inhalation of sphingosine or acid ceramidase.

    Synopsis

    Sphingosine functions as an important anti‐bacterial agent in healthy airways but this defence mechanism is lost in cystic fibrosis. The sensitivity of cystic fibrosis mice to infection can be corrected by inhalation of sphingosine or acid ceramidase.

    • Sphingosine is present on the luminal side of trachea and bronchi epithelia in healthy individuals.

    • Sphingosine level is reduced on trachea and bronchi epithelia in diseases such as cystic fibrosis or in mice lacking ceramide synthase 2.

    • Acid ceramidase or sphingosine inhalation corrects sphingosine levels in cystic fibrosis and ceramide synthase 2‐deficient mice, prevents their infection with Pseudomonas aeruginosa and cures an existing Pseudomonas aeruginosa infection.

    • Sphingosine kills a broad spectrum of pathogens at nanomolar to low micromolar concentrations including Pseudomomas aeruginosa, Acinetobacter baumannii, Haemophilus influenzae, Moraxella catarrhalis and Burkholderia cepacia.

    • cystic fibrosis
    • long chain base
    • lung infection
    • Pseudomonas aeruginosa
    • sphingosine
    • Received March 17, 2014.
    • Revision received July 10, 2014.
    • Accepted July 11, 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.

    Yael Pewzner‐Jung, Shaghayegh Tavakoli Tabazavareh, Heike Grassmé, Katrin Anne Becker, Lukasz Japtok, Jörg Steinmann, Tammar Joseph, Stephan Lang, Burkhard Tuemmler, Edward H Schuchman, Alex B Lentsch, Burkhard Kleuser, Michael J Edwards, Anthony H Futerman, Erich Gulbins
  • Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB
    1. Vinicia A Polito1,,
    2. Hongmei Li1,,
    3. Heidi Martini‐Stoica1,2,3,,
    4. Baiping Wang1,4,
    5. Li Yang1,
    6. Yin Xu1,
    7. Daniel B Swartzlander1,
    8. Michela Palmieri4,5,
    9. Alberto di Ronza4,5,
    10. Virginia M‐Y Lee6,
    11. Marco Sardiello4,5,
    12. Andrea Ballabio4,5,7 and
    13. Hui Zheng*,1,3,4
    1. 1Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA
    2. 2Interdepartmental Program of Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
    3. 3Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA
    4. 4Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
    5. 5Dan and Jan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
    6. 6Department of Pathology and Lab Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    7. 7Department of Translational Medical Sciences, Section of Pediatrics, Telethon Institute of Genetics and Medicine Federico II University, Naples, Italy
    1. *Corresponding author. Tel: +1 713 798 1568; Fax: +1 713 798 1610; E‐mail: huiz{at}bcm.edu
    1. These authors contributed equally to this work

    The autophagy and lysosomal Transcription Factor EB (TFEB) reduces neurofibrillary tangle pathology and rescues behavioral and synaptic deficits and neurodegeneration in the Tau mouse model. This effect requires lysosomal activity and in vitro evidence highlight PTEN as a TFEB‐target.

    Synopsis

    The autophagy and lysosomal Transcription Factor EB (TFEB) reduces neurofibrillary tangle pathology and rescues behavioral and synaptic deficits and neurodegeneration in the Tau mouse model. This effect requires lysosomal activity and in vitro evidence highlight PTEN as a TFEB‐target.

    • TFEB specifically targets aberrant tau proteins.

    • TFEB potently clears NFT pathology and rescues neurotoxicity in a tauopathy mouse model.

    • PTEN is a novel target of TFEB.

    • Upregulation of PTEN and lysosomal activity may underlie the TFEB effects.

    • Alzheimer's disease
    • tauopathy
    • TFEB
    • PTEN
    • autophagy‐lysosomal pathway
    • Received November 14, 2013.
    • Revision received June 26, 2014.
    • Accepted June 30, 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.

    Vinicia A Polito, Hongmei Li, Heidi Martini‐Stoica, Baiping Wang, Li Yang, Yin Xu, Daniel B Swartzlander, Michela Palmieri, Alberto di Ronza, Virginia M‐Y Lee, Marco Sardiello, Andrea Ballabio, Hui Zheng
  • Principles of targeting endothelial cell metabolism to treat angiogenesis and endothelial cell dysfunction in disease
    1. Jermaine Goveia1,2,
    2. Peter Stapor1,2 and
    3. Peter Carmeliet*,1,2
    1. 1Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven, Belgium
    2. 2Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center VIB, Leuven, Belgium
    1. *Corresponding author. Tel: +32 16 37 32 02; Fax: +32 16 37 25 85; E‐mail: peter.carmeliet{at}vib-kuleuven.be

    An comprehensive overview of the alterations of endothelial cell metabolism in disease, and of the potential metabolic targets and strategies to reverse their dysfunction and inhibit angiogenesis.

    • angiogenesis
    • endothelial cell dysfunction
    • metabolism
    • Received April 8, 2014.
    • Revision received June 14, 2014.
    • Accepted July 3, 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.

    Jermaine Goveia, Peter Stapor, Peter Carmeliet
  • The inwardly rectifying K+ channel KIR7.1 controls uterine excitability throughout pregnancy
    1. Conor McCloskey1,
    2. Cara Rada2,
    3. Elizabeth Bailey1,
    4. Samantha McCavera1,
    5. Hugo A van den Berg3,
    6. Jolene Atia1,
    7. David A Rand3,
    8. Anatoly Shmygol1,
    9. Yi‐Wah Chan1,
    10. Siobhan Quenby1,
    11. Jan J Brosens1,
    12. Manu Vatish1,
    13. Jie Zhang1,
    14. Jerod S Denton4,
    15. Michael J Taggart5,
    16. Catherine Kettleborough6,
    17. David Tickle6,
    18. Jeff Jerman6,
    19. Paul Wright6,
    20. Timothy Dale7,
    21. Srinivasan Kanumilli7,
    22. Derek J Trezise7,
    23. Steve Thornton8,
    24. Pamela Brown9,
    25. Roberto Catalano9,
    26. Nan Lin10,
    27. Sarah K England2 and
    28. Andrew M Blanks*,1
    1. 1Division of Reproductive Health, Clinical Sciences Research Laboratories, Warwick Medical School University of Warwick, Coventry, UK
    2. 2Division of Basic Science Research, Department of Obstetrics and Gynecology, School of Medicine Washington University in St. Louis,, St. Louis, MO, USA
    3. 3Warwick Systems Biology & Mathematics Institute University of Warwick, Coventry, UK
    4. 4Vanderbilt Institute of Chemical Biology, Vanderbilt Institute for Global Health Vanderbilt University School of Medicine Medical Center North, Nashville, TN, USA
    5. 5Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
    6. 6Centre for Therapeutics and Discovery, Medical Research Council Technologies, London, UK
    7. 7BioPark, Essen BioScience Ltd, Welwyn Garden City, Hertfordshire, UK
    8. 8Exeter Medical School, Exeter, UK
    9. 9MRC Centre for Reproductive Health (CRH), Queen's Medical Research Institute University of Edinburgh, Edinburgh, UK
    10. 10Department of Mathematics, Washington University, St. Louis, MO, USA
    1. *Corresponding author. Tel: +44 2476968703; Fax: +44 2476968653; E‐mail: andrew.blanks{at}warwick.ac.uk

    Only few effective treatments can manipulate uterine contractility for the prevention of dystocia, preterm labor or post‐partum hemorrhage. This study reveals Kir7.1 channel as a potential target for increasing uterine contractions and identifies novel Kir7.1 inhibitors.

    Synopsis

    Only few effective treatments can manipulate uterine contractility for the prevention of dystocia, preterm labor or post‐partum hemorrhage. This study reveals Kir7.1 channel as a potential target for increasing uterine contractions and identifies novel Kir7.1 inhibitors.

    • A genome‐wide scan of all known potassium channels combined with computational modeling identified Kir7.1 as a potentially useful therapeutic target.

    • Kir7.1 expression increases in mid gestation and declines towards the onset of labor in mice and humans.

    • Kir7.1 inhibition in vitro and in vivo increases uterine contractility.

    • Novel inhibitors of Kir7.1 induce contractions of greater magnitude than a commonly used uterine stimulant oxytocin.

    • pregnancy
    • parturition
    • potassium channels
    • uterus
    • myometrium
    • Received February 6, 2014.
    • Revision received June 13, 2014.
    • Accepted July 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.

    Conor McCloskey, Cara Rada, Elizabeth Bailey, Samantha McCavera, Hugo A van den Berg, Jolene Atia, David A Rand, Anatoly Shmygol, Yi‐Wah Chan, Siobhan Quenby, Jan J Brosens, Manu Vatish, Jie Zhang, Jerod S Denton, Michael J Taggart, Catherine Kettleborough, David Tickle, Jeff Jerman, Paul Wright, Timothy Dale, Srinivasan Kanumilli, Derek J Trezise, Steve Thornton, Pamela Brown, Roberto Catalano, Nan Lin, Sarah K England, Andrew M Blanks
  • Long‐term therapeutic silencing of miR‐33 increases circulating triglyceride levels and hepatic lipid accumulation in mice
    1. Leigh Goedeke1,2,3,4,,
    2. Alessandro Salerno3,4,,
    3. Cristina M Ramírez1,2,3,4,
    4. Liang Guo3,4,
    5. Ryan M Allen5,
    6. Xiaoke Yin6,
    7. Sarah R Langley6,
    8. Christine Esau7,
    9. Amarylis Wanschel3,4,
    10. Edward A Fisher3,4,
    11. Yajaira Suárez1,2,3,4,
    12. Angel Baldán5,
    13. Manuel Mayr6 and
    14. Carlos Fernández‐Hernando*,1,2,3,4
    1. 1Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
    2. 2Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine Yale University School of Medicine, New Haven, CT, USA
    3. 3Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA
    4. 4Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA
    5. 5Edward A. Doisy Department of Biochemistry and Molecular Biology, Center for Cardiovascular Research, Saint Louis University School of Medicine, Saint Louis, MO, USA
    6. 6King's British Heart Foundation Centre, King's College London, London, UK
    7. 7Regulus Therapeutics, San Diego, CA, USA
    1. *Corresponding author. Tel: +1 203 737 4615; Fax: +1 203 737 2290; E‐mail: carlos.fernandez{at}yale.edu
    1. These authors contributed equally to this work.

    Although short‐term anti‐miR‐33 therapy was reported to increase circulating HDL‐cholesterol and reduce atherosclerosis, long‐term adverse effects are here shown for the 1st time in mice fed a high‐fat‐diet to result in hypertriglyerimedia and moderate hepatic steatosis.

    Synopsis

    Although short‐term anti‐miR‐33 therapy was reported to increase circulating HDL‐cholesterol and reduce atherosclerosis, long‐term adverse effects are here shown for the first time in mice fed a high‐fat diet to result in hypertriglyceridemia and moderate hepatic steatosis.

    • The effect of long‐term inhibition of miR‐33 was determined in mice fed a chow diet and high‐fat diet.

    • Chronic therapeutic silencing of miR‐33 increased circulating triglycerides and lipid accumulation in the livers of mice fed a high‐fat diet.

    • miR‐33 inhibition raised the expression of genes involved in fatty acid synthesis and lipid metabolism.

    • Further studies are warranted to understand the complex gene regulatory network controlled by miR‐33.

    • cholesterol
    • fatty acids
    • hepatic steatosis
    • microRNA
    • Received March 8, 2014.
    • Revision received June 18, 2014.
    • Accepted June 26, 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.

    Leigh Goedeke, Alessandro Salerno, Cristina M Ramírez, Liang Guo, Ryan M Allen, Xiaoke Yin, Sarah R Langley, Christine Esau, Amarylis Wanschel, Edward A Fisher, Yajaira Suárez, Angel Baldán, Manuel Mayr, Carlos Fernández‐Hernando
  • Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions
    1. Marten A Hoeksema1,
    2. Marion JJ Gijbels1,2,3,
    3. Jan Van den Bossche1,
    4. Saskia van der Velden1,
    5. Ayestha Sijm1,
    6. Annette E Neele1,
    7. Tom Seijkens1,
    8. J Lauran Stöger1,
    9. Svenja Meiler1,
    10. Marieke CS Boshuizen1,
    11. Geesje M Dallinga‐Thie4,
    12. Johannes HM Levels4,
    13. Louis Boon5,
    14. Shannon E Mullican6,
    15. Nathanael J Spann7,
    16. Jack P Cleutjens2,
    17. Chris K Glass7,
    18. Mitchell A Lazar6,
    19. Carlie JM de Vries1,
    20. Erik AL Biessen2,
    21. Mat JAP Daemen8,
    22. Esther Lutgens1,9 and
    23. Menno PJ de Winther*,1
    1. 1Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    2. 2Department of Pathology, Maastricht University, Maastricht, The Netherlands
    3. 3Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands
    4. 4Department of Vascular and Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    5. 5Bioceros BV, Utrecht, The Netherlands
    6. 6Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
    7. 7Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA
    8. 8Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    9. 9Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian's University, Munich, Germany
    1. *Corresponding author. Tel: +31 20 5666762; E‐mail: m.dewinther{at}amc.uva.nl

    Hdac3 is shown to be an important modulator of the fibrotic phenotype of macrophages in atherosclerosis and, in humans, the expression of Hdac3 is linked to plaque vulnerability to rupture.

    Synopsis

    Hdac3 is shown to be an important modulator of the fibrotic phenotype of macrophages in atherosclerosis and, in humans, the expression of Hdac3 is linked to plaque vulnerability to rupture.

    • Myeloid Hdac3 deficiency promotes collagen deposition in atherosclerosis

    • Macrophage Hdac3 deletion enhances TGF‐β secretion thereby increasing collagen production by vascular smooth muscle cells and results in improved lipid handling by de‐repression of PPARγ and LXR responses

    • In humans, Hdac3 is upregulated in ruptured atherosclerotic lesions and is associated with inflammatory macrophages

    • Fine‐tuning of the macrophage phenotype by altering the epigenetic landscape can be applied to affect atherosclerotic disease outcome

    • atherosclerosis
    • epigenetics
    • fibrosis
    • lipids
    • macrophages
    • Received April 14, 2014.
    • Revision received June 6, 2014.
    • Accepted June 10, 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.

    Marten A Hoeksema, Marion JJ Gijbels, Jan Van den Bossche, Saskia van der Velden, Ayestha Sijm, Annette E Neele, Tom Seijkens, J Lauran Stöger, Svenja Meiler, Marieke CS Boshuizen, Geesje M Dallinga‐Thie, Johannes HM Levels, Louis Boon, Shannon E Mullican, Nathanael J Spann, Jack P Cleutjens, Chris K Glass, Mitchell A Lazar, Carlie JM de Vries, Erik AL Biessen, Mat JAP Daemen, Esther Lutgens, Menno PJ de Winther