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The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology.
Linnerbauer, Mathias; Lößlein, Lena; Vandrey, Oliver; Peter, Anne; Han, Yanan; Tsaktanis, Thanos; Wogram, Emile; Needhamsen, Maria; Kular, Lara; Nagel, Lisa; Zissler, Julia; Andert, Marie; Meszaros, Lisa; Hanspach, Jannis; Zuber, Finnja; Naumann, Ulrike J; Diebold, Martin; Wheeler, Michael A; Beyer, Tobias; Nirschl, Lucy; Cirac, Ana; Laun, Frederik B; Günther, Claudia; Winkler, Jürgen; Bäuerle, Tobias; Jagodic, Maja; Hemmer, Bernhard; Prinz, Marco; Quintana, Francisco J; Rothhammer, Veit.
Afiliación
  • Linnerbauer M; Department of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Lößlein L; Department of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Vandrey O; Department of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Peter A; Department of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Han Y; Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden.
  • Tsaktanis T; Department of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Wogram E; Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Needhamsen M; Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden.
  • Kular L; Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden.
  • Nagel L; Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Zissler J; Department of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Andert M; Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Meszaros L; Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Hanspach J; Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Zuber F; Department of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Naumann UJ; Department of Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Diebold M; Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Wheeler MA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Beyer T; The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Nirschl L; Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • Cirac A; Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • Laun FB; Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • Günther C; Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Winkler J; Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Bäuerle T; Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Jagodic M; Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Erlangen, Germany.
  • Hemmer B; Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine, Stockholm, Sweden.
  • Prinz M; Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • Quintana FJ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • Rothhammer V; Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Nat Immunol ; 25(3): 432-447, 2024 Mar.
Article en En | MEDLINE | ID: mdl-38409259
ABSTRACT
Central nervous system (CNS)-resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including multiple sclerosis (MS). Several studies have demonstrated the involvement of pro-inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from patients with MS in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of autoimmune neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a modulator of autoimmune CNS inflammation and potential therapeutic target in MS.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Astrocitos / Esclerosis Múltiple Límite: Animals / Humans Idioma: En Revista: Nat Immunol Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Astrocitos / Esclerosis Múltiple Límite: Animals / Humans Idioma: En Revista: Nat Immunol Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos