Shane A Liddelow 1 , 2 , Kevin A Guttenplan 1 , Laura E Clarke 1 , Frederick C Bennett 1 , 3 , Christopher J Bohlen 2 , Lucas Schirmer 4 , 5 , Mariko L Bennett 1 , Alexandra E Münch 1 , Won-Suk Chung 6 , Todd C Peterson 7 , Daniel K Wilton 8 , Arnaud Frouin 8 , Brooke A Napier 9 , Nikhil Panicker 10 , 11 , 12 , Manoj Kumar 10 , 11 , 12 , Marion S Buckwalter 7 , David H Rowitch 16 , 17 , Valina L Dawson 10 , 11 , 12 , 13 , 14 , Ted M Dawson 10 , 11 , 12 , 14 , 15 , Beth Stevens 8 , Ben A Barres 1
18 January 2017
Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease but their role is poorly understood. Here we show that A1 reactive astrocytes are induced by classically-activated neuroinflammatory microglia. We show that activated microglia induce A1s by secreting Il-1α, TNFα, and C1q, and that these cytokines together are necessary and sufficient to induce A1s. A1s lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when A1 formation is blocked. Finally, we show that A1s are highly present in human neurodegenerative diseases including Alzheimer’s, Huntington’s, Parkinson’s, ALS, and Multiple Sclerosis. Taken together these findings explain why CNS neurons die after axotomy, strongly suggest that A1s help to drive death of neurons and oligodendrocytes in neurodegenerative disorders, and point the way forward for developing new treatments of these diseases.