Neurotoxic reactive astrocytes are induced by activated microglia

By S. A. Liddelow, Kevin A. Guttenplan, Laura E Clarke, F. C. Bennett, Christopher J. Bohlen, Lucas Schirmer, Mariko L. Bennett, Alexandra E. Münch, Won-Suk Chung, Todd C. Peterson and 11 more. Nature, 2017

3,168 citations recorded by the source corpus.

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.

Subfields: Immunology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/34c62e74e8a9337e85c47596fbccb366e5fd206b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Chao Gao
2. Shengdi Chen
3. Yuyan Tan
4. Jingwen Jiang
5. J. Long
6. S. A. Liddelow
7. D. Holtzman
8. B. Barres

In Neurology

1. N. J. Allen
2. Chao Gao
3. Shengdi Chen
4. Yuyan Tan
5. Jingwen Jiang
6. S. A. Liddelow
7. L. Clarke
8. B. Barres

In Physiology

1. J. Long
2. S. A. Liddelow
3. N. J. Allen
4. D. Holtzman
5. B. Barres
6. Berislav Zlokovic

Citations in the corpus

• The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain (2018, background): “Interestingly, the mechanism of synapse elimination involves complement tagging of synapses for phagocytosis by microglia, showing a potential for cross-talk between different glial cell types in aging, which may be bidirectional (Liddelow et al., 2017; Schafer et al., 2012).”
• Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023, background): “112 Once A1 astrocytes are induced, they lose their essential functions such as supporting neuronal survival, and they also promote neuroin fl ammation, which contributes to the progression of neurodegenerative diseases.”
• Normal aging induces A1-like astrocyte reactivity (2018, background): “These included genes specifically upregulated by neuroinflammation (A1-specific) or ischemia (A2-specific), or those induced by both neuroinflammation and ischemia (pan-reactive genes) (9, 20).”
• Endoplasmic reticulum stress: molecular mechanism and therapeutic targets (2023, background): “94 CHOP and BiP are localized in GFAP-positive astrocytes with the OPTN E50K mutation, indicating ER stress involvement in the activation of neurotoxic reactive astrocytes and RGCs loss.”
• Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, positive): “, 2018) or secrete indirect mediators that stimulate astrocytes to secrete a neurotoxic substance (Liddelow et al., 2017).”