Microglia-Induced Reactive Astrocytes — Rgcs, Cortical Neurons, Spinal Motor Neurons and Mature Oligo Toxic Players in Neurological Disease? Dendrocytes

RESEARCH HIGHLIGHTS

Nature Reviews Neurology | Published online 3 Feb 2017; doi:10.1038/nrneurol.2017.17

NEUROIMMUNOLOGY Importantly, media conditioned by A1 astrocytes was highly toxic to a variety of neuronal cells, including Microglia-induced reactive astrocytes — RGCs, cortical neurons, spinal motor neurons and mature oligo toxic players in neurological disease? dendrocytes. This action could not be blocked with antibodies against Astrocytes can lose their normal neurons,” remarks lead author of the IL-1α, TNF or C1q, indicating the protective features and take on a new study, Shane Liddelow. “We are presence of an as-yet unknown toxic neurotoxic function that might play now learning of the important role entity. Furthermore, crushing of a part in CNS injury and neuro that astrocytes and microglia play in the optic nerve in rats increased A1 degeneration, according to a new neurodegeneration.” astrocyte generation in the animals study published in Nature. The team, Barres and his team previously and was associated with the death of led by Ben Barres, found that acti identified two classes of reactive the injured neurons. However, this vated microglia induce the formation astrocytes: A1 astrocytes, which they effect could be blocked by antibodies of harmful A1 astrocytes in areas that predicted to have a harmful role, and against IL-1a, TNF and C1q, which are vulnerable to cell death in several A2 astrocytes, which they predicted halted the generation of A1 astrocytes neurodegenerative disorders. to have a protective role. In their new and delayed neuronal death. Astrocytes fulfil numerous crucial work, they set out to characterize the Finally, Barres and colleagues functions in the CNS, such as the pro potentially destructive A1 astrocytes. investigated whether A1 astrocytes vision of trophic support to neurons, The researchers found that A1 might be important in human neuro clearance of debris, and modulation astrocytes were generated in wild- degenerative disease. Immunostaining of synapse formation and function. a broad type mice after injection of lipopoly for C3, a marker of A1 astrocytes, was In injury and disease, these cells can range of brain saccharide (LPS), which activates positive in postmortem brain tissue transform into ‘reactive’ astrocytes, disorders might microglia. However, LPS injection in from patients who had Alzheimer dis which can be neuroprotective or Csf1r-knockout mice that lack micro ease, Huntington disease, Parkinson neurotoxic in different circumstances. be treatable glia did not produce A1 astrocytes, disease, amyotrophic lateral sclerosis However, the function of reactive by blocking suggesting that activated microglia or multiple sclerosis. “What was most astrocytes in disease, and whether astrocytes’ induce A1 astrocytes. exciting and remarkable was that once therapies could be targeted to these Media conditioned by LPS- we were able to visualize these reactive cells, remains unclear. metamorphosis activated microglia in vitro, but not astrocytes, we saw that they were “For so many years, the focus of into toxic cells media from nonactivated microglia, largely present in those brain regions neurodegenerative disease treatment also induced the A1 phenotype in associated with neurodegeneration” and research has mostly targeted cultured astrocytes. IL-1α, tumour explains Liddelow. necrosis factor (TNF) and compli The team think that these cells ment factor C1q were all upregulated could represent an important target after microglial activation, and the for future treatments. “Our results addition of neutralizing antibodies show that a broad range of brain dis against these molecules to block orders might be treatable by blocking their signalling prevented microglia- astrocytes’ metamorphosis into toxic conditioned media from inducing cells, or by pharmaceutically coun the A1 phenotype. tering the neuron-killing toxin that Barres and co-workers went on harmful astrocytes almost certainly to show that A1 astrocytes lose their secrete,” concludes Liddelow. “We usual helpful functions and take on strongly believe that the develop a toxic role. When cultured with ment of more-effective drugs to treat A1 astrocytes, retinal ganglion cells astrocyte reactivity will help to treat (RGCs) made 50% fewer connections a broad range of neurodegenerative than those grown with nonactivated diseases.” astrocytes, and their remaining Charlotte Ridler

synaptic connections were weaker. ORIGINAL ARTICLE Liddelow, S. A. et al. In addition, A1 astrocytes had a Neurotoxic reactive astrocytes are induced by decreased ability to phagocytose activated microglia. Nature http://dx.doi. False-colour image of mouse astrocytes following activation with IL-1α, tumour org/10.1038/nature21029 (2017) necrosis factor and compliment factor C1q in vitro. Image courtesy of S. A. Liddelow. myelin debris and synaptosomes.