Neurotoxic reactive astrocytes are induced by activated microglia.
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.
|Year of Publication||
2017 01 26
|PubMed Central ID||
R01 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