Neurotoxic reactive astrocytes are induced by activated microglia

Shane A. Liddelow (), Kevin A. Guttenplan, Laura E. Clarke, Frederick C. Bennett, Christopher J. Bohlen, Lucas Schirmer, Mariko L. Bennett, Alexandra E. Münch, Won-Suk Chung, Todd C. Peterson, Daniel K. Wilton, Arnaud Frouin, Brooke A. Napier, Nikhil Panicker, Manoj Kumar, Marion S. Buckwalter, David H. Rowitch, Valina L. Dawson, Ted M. Dawson, Beth Stevens and Ben A. Barres
Additional contact information
Shane A. Liddelow: Stanford University, School of Medicine
Kevin A. Guttenplan: Stanford University, School of Medicine
Laura E. Clarke: Stanford University, School of Medicine
Frederick C. Bennett: Stanford University, School of Medicine
Christopher J. Bohlen: University of Melbourne
Lucas Schirmer: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco
Mariko L. Bennett: Stanford University, School of Medicine
Alexandra E. Münch: Stanford University, School of Medicine
Won-Suk Chung: Korea Advanced Institute of Science and Technology (KAIST)
Todd C. Peterson: Stanford University, School of Medicine
Daniel K. Wilton: F. M. Kirby Neurobiology Center, Boston Children’s Hospital
Arnaud Frouin: F. M. Kirby Neurobiology Center, Boston Children’s Hospital
Brooke A. Napier: Stanford University, School of Medicine
Nikhil Panicker: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
Manoj Kumar: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
Marion S. Buckwalter: Stanford University, School of Medicine
David H. Rowitch: University of California San Francisco
Valina L. Dawson: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
Ted M. Dawson: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine
Beth Stevens: F. M. Kirby Neurobiology Center, Boston Children’s Hospital
Ben A. Barres: Stanford University, School of Medicine

Nature, 2017, vol. 541, issue 7638, 481-487

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature21029

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