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.

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Acknowledgements

We thank R. Vance (UC Berkeley) for gifting Il-1a-/- mice and E. R. Stanley (Albert Einstein College of Medicine) for gifting Csf1r-/- mice. This work was supported by grants from the National Institutes of Health (R01 AG048814, B.A.B.; RO1 DA15043, B.A.B.; P50 NS38377, V.L.D. and T.M.D.) Christopher and Dana Reeve Foundation (B.A.B.), the Novartis Institute for Biomedical Research (B.A.B.), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (B.A.B.), the JPB Foundation (B.A.B., T.M.D.), the Cure Alzheimer’s Fund (B.A.B.), the Glenn Foundation (B.A.B.), the Esther B O’Keeffe Charitable Foundation (B.A.B.), the Maryland Stem Cell Research Fund (2013-MSCRFII-0105-00, V.L.D.; 2012-MSCRFII-0268-00, T.M.D.; 2013-MSCRFII-0105-00, T.M.D.; 2014-MSCRFF-0665, M.K.). S.A.L. was supported by a postdoctoral fellowship from the Australian National Health and Medical Research Council (GNT1052961), and the Glenn Foundation Glenn Award. L.E.C. was funded by a Merck Research Laboratories postdoctoral fellowship (administered by the Life Science Research Foundation). W.-S.C. was supported by a career transition grant from NEI (K99EY024690). C.J.B. was supported by a postdoctoral fellowship from Damon Runyon Cancer Research Foundation (DRG-2125-12). L.S. was supported by a postdoctoral fellowship from the German Research Foundation (DFG, SCHI 1330/1-1). T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. The authors (N.P., M.K., V.L.D. and T.M.D.) acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the Foundation’s Parkinson’s Disease Program M-2014. We thank the Stanford Alzheimer’s disease research Centre (AG047366), the Stanford Health Care Brain Bank, The Arizona Ageing & Disability Resource Centers (AG019610) and Banner Sun Health for providing control and AD brain samples. We thank R. Reynolds and D. Gveric for providing control and MS brain samples from the UK Multiple Sclerosis Tissue Bank, funded by the Multiple Sclerosis Society of Great Britain and Northern Ireland (registered charity 207495). We would like to thank O. Pletnikova and J. C. Troncoso from the Department of Pathology, Johns Hopkins University School of Medicine, for providing control and PD human sections. We thank the Neurological Foundation of New Zealand Human Brain Bank at the University of Auckland for Control and HD tissue sections for IHC analysis. We thank R. Myers at Boston University Medical Centre for control and HD tissue for q-RTPCR analysis. We thank J. Trojanoswki at the University of Pennsylvania Institute on Aging for AD and ALS tissue samples for in situ analysis. We thank A. Mosberger and A. Rosenthal for careful review of the manuscript. We thank T. Jessell and T. Maniatis for their insightful discussions on motor neuron subtypes. We thank V. and S. Coates for their generous support.

Author information

Affiliations

  1. Department of Neurobiology, Stanford University, School of Medicine, Stanford, California 94305, USA

    • Shane A. Liddelow
    • , Kevin A. Guttenplan
    • , Laura E. Clarke
    • , Frederick C. Bennett
    • , Mariko L. Bennett
    • , Alexandra E. Münch
    •  & Ben A. Barres
  2. Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria 3010, Australia

    • Shane A. Liddelow
    •  & Christopher J. Bohlen
  3. Department of Psychiatry and Behavioral Sciences, Stanford University, School of Medicine, Stanford, California 94305, USA

    • Frederick C. Bennett
  4. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA

    • Lucas Schirmer
  5. Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich 81675, Germany

    • Lucas Schirmer
  6. Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea

    • Won-Suk Chung
  7. Department of Neurology & Neurological Sciences, Stanford University, School of Medicine, Stanford, California 94305, USA

    • Todd C. Peterson
    •  & Marion S. Buckwalter
  8. Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, Massachusetts 02115, USA

    • Daniel K. Wilton
    • , Arnaud Frouin
    •  & Beth Stevens
  9. Department of Microbiology and Immunology, Stanford University, School of Medicine, Stanford, California 94305, USA

    • Brooke A. Napier
  10. Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Nikhil Panicker
    • , Manoj Kumar
    • , Valina L. Dawson
    •  & Ted M. Dawson
  11. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Nikhil Panicker
    • , Manoj Kumar
    • , Valina L. Dawson
    •  & Ted M. Dawson
  12. Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685, USA

    • Nikhil Panicker
    • , Manoj Kumar
    • , Valina L. Dawson
    •  & Ted M. Dawson
  13. Departments of Pediatrics and Neurosurgery, University of California San Francisco, San Francisco, California 94143, USA

    • David H. Rowitch
  14. Department of Paediatrics, University of Cambridge, Cambridge CB2 0AH, UK

    • David H. Rowitch
  15. Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Valina L. Dawson
  16. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Valina L. Dawson
    •  & Ted M. Dawson
  17. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Ted M. Dawson

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Contributions

S.A.L. and B.A.B. designed the experiments and wrote the paper. All authors reviewed and edited the manuscript. S.A.L. performed experiments and analysed data. K.G. performed proliferation assays and single-cell analysis. L.E.C. performed and analysed electrophysiology recordings and W.-S.C. performed and analysed in vivo astrocyte synapse pruning experiments. M.L.B. and S.A.L. performed optic nerve crushes. B.A.N. performed and analysed bacterial experiments. F.C.B. performed and analysed FACS experiments. T.C.P. performed stroke (MCAO) experiments. C.J.B. developed microglia culture systems. N.P. and M.K. differentiated hES cells to dopaminergic neurons for toxicity assays. Immunohistochemistry and analysis of human tissue was performed by L.S. (MS samples), S.A.L., D.K.W. and A.F. (AD), D.K.W. and A.F. (HD and ALS samples), and N.P. and M.K. (PD samples). qPCR analysis of human tissue was performed by S.A.L. (AD, HD, ALS and PD samples) and L.S. (MS samples). A.E.M. and K.G. provided technical support.

Competing interests

B.A.B. is a co-founder of Annexon Biosciences Inc., a company working to make new drugs for treatment of neurological diseases.

Corresponding author

Correspondence to Shane A. Liddelow.

Reviewer Information Nature thanks M. Freeman, S. Koizumi and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature21029

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