title: Neurotoxic reactive astrocytes are induced by activated microglia.
abstract: Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases.
authors.affiliation: Department of Neurobiology, Stanford University, School of Medicine, Stanford, California 94305, USA.|Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Liddelow
authors.affiliation: Department of Neurobiology, Stanford University, School of Medicine, Stanford, California 94305, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Guttenplan
authors.affiliation: Department of Neurobiology, Stanford University, School of Medicine, Stanford, California 94305, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Clarke
authors.affiliation: Department of Neurobiology, Stanford University, School of Medicine, Stanford, California 94305, USA.|Department of Psychiatry and Behavioral Sciences, Stanford University, School of Medicine, Stanford, California 94305, USA.
authors.forename: Frederick C
authors.initials: FC
authors.lastname: Bennett
authors.affiliation: Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bohlen
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA.|Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich 81675, Germany.
authors.forename: Lucas
authors.initials: L
authors.lastname: Schirmer
authors.affiliation: Department of Neurobiology, Stanford University, School of Medicine, Stanford, California 94305, USA.
authors.forename: Mariko L
authors.initials: ML
authors.lastname: Bennett
authors.affiliation: Department of Neurobiology, Stanford University, School of Medicine, Stanford, California 94305, USA.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Münch
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea.
authors.forename: Won-Suk
authors.initials: WS
authors.lastname: Chung
authors.affiliation: Department of Neurology &Neurological Sciences, Stanford University, School of Medicine, Stanford, California 94305, USA.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Peterson
authors.affiliation: Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Wilton
authors.affiliation: Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Frouin
authors.affiliation: Department of Microbiology and Immunology, Stanford University, School of Medicine, Stanford, California 94305, USA.
authors.forename: Brooke A
authors.initials: BA
authors.lastname: Napier
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Panicker
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685, USA.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Department of Neurology &Neurological Sciences, Stanford University, School of Medicine, Stanford, California 94305, USA.
authors.forename: Marion S
authors.initials: MS
authors.lastname: Buckwalter
authors.affiliation: Departments of Pediatrics and Neurosurgery, University of California San Francisco, San Francisco, California 94143, USA.|Department of Paediatrics, University of Cambridge, Cambridge CB2 0AH, UK.
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685, USA.|Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685, USA.|Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.affiliation: Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Stevens
authors.affiliation: Department of Neurobiology, Stanford University, School of Medicine, Stanford, California 94305, USA.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Barres
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000145:classification* / Q000378:metabolism / Q000473:pathology*; D019771:Axotomy; D018929:Cell Culture Techniques; D016923:Cell Death; D002470:Cell Survival; D002490:Central Nervous System / Q000473:pathology*; D015922:Complement C1q / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D007249:Inflammation / Q000473:pathology; D053582:Interleukin-1alpha / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D019636:Neurodegenerative Diseases / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D009836:Oligodendroglia / Q000473:pathology; D010587:Phagocytosis; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000473:pathology; D014118:Toxins, Biological / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053582:Interleukin-1alpha; D014118:Toxins, Biological; D014409:Tumor Necrosis Factor-alpha; D015922:Complement C1q