The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology

Mathias Linnerbauer, Lena Lößlein, Oliver Vandrey, Anne Peter, Yanan Han, Thanos Tsaktanis, Emile Wogram, Maria Needhamsen, Lara Kular, Lisa Nagel, Julia Zissler, Marie Andert, Lisa Meszaros, Jannis Hanspach, Finnja Zuber, Ulrike J. Naumann, Martin Diebold, Michael A. Wheeler, Tobias Beyer, Lucy NirschlAna Cirac, Frederik B. Laun, Claudia Günther, Jürgen Winkler, Tobias Bäuerle, Maja Jagodic, Bernhard Hemmer, Marco Prinz, Francisco J. Quintana, Veit Rothhammer

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish
Pages (from-to)432-447
Number of pages16
JournalNature Immunology
Volume25
Issue number3
DOIs
StatePublished - Mar 2024
Externally publishedYes

Fingerprint

Dive into the research topics of 'The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology'. Together they form a unique fingerprint.

Cite this