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WCN 2021 | Mechanisms used by astrocytes to control CNS pathology

Francisco Quintana, PhD, Brigham and Women’s Hospital, Boston, MA, explains how astrocytes can contribute to CNS pathology in multiple sclerosis (MS). It is known that astrocytes can gain neurotoxic functions by activating neurotoxic activities of central nervous system (CNS)-resident cells, and by recruiting peripheral inflammatory cells to the CNS via chemokine production. Ongoing efforts are trying to characterize astrocyte heterogeneity in MS and build up a picture of how specific subtypes participate in MS pathology. Different astrocyte subtypes either promoting or limiting neurotoxicity have been identified. Cell-cell interactions have been recognized as a central mechanism promoting the pathogenic activity of astrocytes. Using a newly developed technique named RABID-seq, Prof. Quintana and his team were able to identify an interaction between microglia and astrocytes that results in the activation of mTOR signaling in astrocytes, thereby activating its neurotoxic functions. This interview took place during the XXV World Congress of Neurology.

Transcript (edited for clarity)

Astrocytes can control and contribute to CNS pathology in multiple ways. First of all, astrocytes perform a lot of functions in the context of homeostasis and health, such as controlling the blood-brain barrier function, providing nutrients to neurons, providing neurotrophic factors. Many of those functions are actually impaired in the context of neurodegeneration. On top of that, astrocytes gain pathogenic activities or activities that promote CNS pathologies, such as the ability to recruit inflammatory and neurotoxic cells from the periphery into the CNS via the production of chemokines, the ability to activate CNS-resident cells so they themselves gain neurotoxic activity via, for example, the production of cytokines...

Astrocytes can control and contribute to CNS pathology in multiple ways. First of all, astrocytes perform a lot of functions in the context of homeostasis and health, such as controlling the blood-brain barrier function, providing nutrients to neurons, providing neurotrophic factors. Many of those functions are actually impaired in the context of neurodegeneration. On top of that, astrocytes gain pathogenic activities or activities that promote CNS pathologies, such as the ability to recruit inflammatory and neurotoxic cells from the periphery into the CNS via the production of chemokines, the ability to activate CNS-resident cells so they themselves gain neurotoxic activity via, for example, the production of cytokines. And finally, astrocytes themselves, they do have neurotoxic activity that, obviously, they can use in order to promote neurodegeneration.

So it is very important to understand if we accept that astrocytes can play multiple roles in the context of neurodegeneration, it’s important to understand what are the pathways that control those functions. And indeed, if we go there, it’s even more important to understand the different subsets of astrocytes that might operate in order to promote and limit inflammation. So over the years, we’ve worked in trying to characterize new subsets of astrocytes. We have been able to characterize what we believe are disease-promoting astrocytes, and also subsets of astrocytes that seem to limit CNS inflammation.

When we focus on those that promote CNS inflammation, we identified, for example, an important role for pollutants, an important role for cell-cell interactions, and important roles, for example, for cytokines in boosting astrocyte pathogenic activities. When we focused specifically in some of those pathways, we recently made the discovery, we developed a new technique, which we call RABID-seq, which allows us to study cell-cell interactions. Because we have identified cell-cell interactions as the central mechanism driving disease-promoting and disease-arresting activities of astrocytes. And by applying this new technique, we were able to identify cell-cell interactions between astrocytes and microglia, mediated by ephrin-B3 expressing microglia and EphB3-expressing astrocytes, as an important factor driving astrocyte pathogenic activities. In mechanistic studies, we actually established that this signaling pathway activates mTOR signaling in astrocytes, and that results in the activation of neurotoxic activities.

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