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 Dawson, Ted M Dawson, Beth StevensBen A. Barres

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)481-487
Number of pages7
JournalNature
Volume541
Issue number7638
DOIs
StatePublished - Jan 26 2017

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Microglia
Astrocytes
Neurons
Oligodendroglia
Neurodegenerative Diseases
Central Nervous System
Nervous System Trauma
Axotomy
Aptitude
Central Nervous System Diseases
Huntington Disease
Amyotrophic Lateral Sclerosis
Phagocytosis
Multiple Sclerosis
Parkinson Disease
Alzheimer Disease
Cytokines

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., ... Barres, B. A. (2017). Neurotoxic reactive astrocytes are induced by activated microglia. Nature, 541(7638), 481-487. https://doi.org/10.1038/nature21029

Neurotoxic reactive astrocytes are induced by activated microglia. / Liddelow, Shane A.; Guttenplan, Kevin A.; Clarke, Laura E.; Bennett, Frederick C.; Bohlen, Christopher J.; Schirmer, Lucas; Bennett, Mariko L.; Münch, Alexandra E.; Chung, Won Suk; Peterson, Todd C.; Wilton, Daniel K.; Frouin, Arnaud; Napier, Brooke A.; Panicker, Nikhil; Kumar, Manoj; Buckwalter, Marion S.; Rowitch, David H.; Dawson, Valina; Dawson, Ted M; Stevens, Beth; Barres, Ben A.

In: Nature, Vol. 541, No. 7638, 26.01.2017, p. 481-487.

Research output: Contribution to journalArticle

Liddelow, SA, Guttenplan, KA, Clarke, LE, Bennett, FC, Bohlen, CJ, Schirmer, L, Bennett, ML, Münch, AE, Chung, WS, Peterson, TC, Wilton, DK, Frouin, A, Napier, BA, Panicker, N, Kumar, M, Buckwalter, MS, Rowitch, DH, Dawson, V, Dawson, TM, Stevens, B & Barres, BA 2017, 'Neurotoxic reactive astrocytes are induced by activated microglia', Nature, vol. 541, no. 7638, pp. 481-487. https://doi.org/10.1038/nature21029
Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017 Jan 26;541(7638):481-487. https://doi.org/10.1038/nature21029
Liddelow, Shane A. ; Guttenplan, Kevin A. ; Clarke, Laura E. ; Bennett, Frederick C. ; Bohlen, Christopher J. ; Schirmer, Lucas ; Bennett, Mariko L. ; Münch, Alexandra E. ; Chung, Won Suk ; Peterson, Todd C. ; Wilton, Daniel K. ; Frouin, Arnaud ; Napier, Brooke A. ; Panicker, Nikhil ; Kumar, Manoj ; Buckwalter, Marion S. ; Rowitch, David H. ; Dawson, Valina ; Dawson, Ted M ; Stevens, Beth ; Barres, Ben A. / Neurotoxic reactive astrocytes are induced by activated microglia. In: Nature. 2017 ; Vol. 541, No. 7638. pp. 481-487.
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