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Nature DOI:10.1038/nature21029

Neurotoxic reactive astrocytes are induced by activated microglia.

Publication TypeJournal Article
Year of Publication2017
AuthorsLiddelow, SA, Guttenplan, KA, Clarke, LE, Bennett, FC, Bohlen, CJ, Schirmer, L, Bennett, ML, Münch, AE, Chung, W-S, Peterson, TC, Wilton, DK, Frouin, A, Napier, BA, Panicker, N, Kumar, M, Buckwalter, MS, Rowitch, DH, Dawson, VL, Dawson, TM, Stevens, B, Barres, BA
JournalNature
Volume541
Issue7638
Pages481-487
Date Published2017 01 26
ISSN1476-4687
KeywordsAnimals, Astrocytes, Axotomy, Cell Culture Techniques, Cell Death, Cell Survival, Central Nervous System, Complement C1q, Disease Progression, Humans, Inflammation, Interleukin-1alpha, Mice, Mice, Inbred C57BL, Microglia, Neurodegenerative Diseases, Neurons, Oligodendroglia, Phagocytosis, Phenotype, Rats, Rats, Sprague-Dawley, Synapses, Toxins, Biological, Tumor Necrosis Factor-alpha
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.

DOI10.1038/nature21029
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28099414?dopt=Abstract

Alternate JournalNature
PubMed ID28099414
PubMed Central IDPMC5404890
Grant ListR01 DA015043 / DA / NIDA NIH HHS / United States
P50 NS038377 / NS / NINDS NIH HHS / United States
R37 NS067525 / NS / NINDS NIH HHS / United States
R37 DA015043 / DA / NIDA NIH HHS / United States
U54 HD090255 / HD / NICHD NIH HHS / United States
R01 AG048814 / AG / NIA NIH HHS / United States