title: Extracellular histone H1 is neurotoxic and drives a pro-inflammatory response in microglia.
abstract: In neurodegenerative conditions and following brain trauma it is not understood why neurons die while astrocytes and microglia survive and adopt pro-inflammatory phenotypes. We show here that the damaged adult brain releases diffusible factors that can kill cortical neurons and we have identified histone H1 as a major extracellular candidate that causes neurotoxicity and activation of the innate immune system. Extracellular core histones H2A, H2B H3 and H4 were not neurotoxic. Innate immunity in the central nervous system is mediated through microglial cells and we show here for the first time that histone H1 promotes their survival, up-regulates MHC class II antigen expression and is a powerful microglial chemoattractant. We propose that when the central nervous system is degenerating, histone H1 drives a positive feedback loop that drives further degeneration and activation of immune defences which can themselves be damaging. We suggest that histone H1 acts as an antimicrobial peptide and kills neurons through mitochondrial damage and apoptosis.
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, UK ; Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, S-901 87, Sweden.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Gilthorpe
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, UK.
authors.forename: Fazal
authors.initials: F
authors.lastname: Oozeer
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Nash
authors.affiliation: Wolfson Centre for Age Related Diseases, King's College London, London, SE1 1UL, UK.
authors.forename: Margarita
authors.initials: M
authors.lastname: Calvo
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
authors.forename: David Lh
authors.initials: DL
authors.lastname: Bennett
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lumsden
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Pini