What Do Reactive Astrocytes Do? Shane A Liddelow Neuroscience Institute & Department of Neuroscience and Physiology; NYU Langone Medical Center, New York, NY, USA
Reactive astrocytes are rapidly generated following brain injuries and neurodegenerative and neuroinflammatory diseases, however their role in trauma and disease states is not well understood. Previously we distinguished two reactive astrocyte subclasses based on the kind of inducing injury. We named these classes “A1” and “A2”. Based on their gene profiles we hypothesized that they were harmful and helpful respectively. We have shown that the harmful A1 reactive astrocytes are induced by classically-activated neuroinflammatory microglia. Specifically, we found that activated microglia induce A1s by secreting Il-1α, TNFα, and C1q, and that these factors together are necessary and sufficient to induce A1s both in vitro and in vivo. A1s have little ability to promote neuronal survival, outgrowth, synaptogenesis or phagocytosis and instead are powerfully toxic to neurons and oligodendrocytes. We further showed that A1s are present in human Alzheimer's disease, Huntington Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis, and that death of axotomized CNS neurons is prevented when A1 formation is blocked with neutralizing antibodies to Il-1α, TNFα, and C1q. Though we had shown that presence of A1 reactive astrocytes was sufficient to induce neuronal and oligodendrocyte cell death in an in vitro and acute in vivo setting, we have been interested if the chronic setting common to neurodegenerative and demyelinating diseases could also cause the death of CNS cells. We now show the role of A1 neurotoxic reactive astrocytes in the context of neurodegeneration in both acute (trauma) and chronic (bead injection induced glaucoma) models in the mouse retina. We use high throughput microfluidic qPCR and immunohistochemistry for markers of retinal ganglion cells, as well as live/dead stain analysis of live cell imaging in vitro to determine activation state of astrocytes, and gross viability measurements of neurons and oligodendrocytes. To block formation of A1 astrocytes we employ Il1a-/-Tnf-/-C1qa-/- mutant mice, as well as injection of neutralizing antibodies to IL1α, TNFα, and C1q directly into the vitreous of the eye. We show that in both the acute (trauma) and chronic (glaucoma) model we can drive death of neurons in the retina. In addition, we can preserve neuronal health and stop death of these cells by modulating astrocyte reactivity. What remains to be seen is if preserved neurons retain normal functional activity, and if preservation of damaged myelin leads to a improved functional outcome. Taken together our findings strongly suggest that A1s drive death of neurons in neurodegenerative disorders, and point the way forward for developing new treatments for these diseases.