167 Astrocyte and Oligodendrocyte Crosstalk injury induces astrocyte reactivity. Upon activation, astrocytes secrete factors e.g. TNF-α, IL-1β, IL-6, brain derived neurotrophic factor (BDNF), leukemia inhibitory factor (LIF), CCL2, and CXCL103,25,119,123,132. These factors play a critical role in generating the immune responses during infection or damage, but also lead to collateral damage of oligodendrocytes and OPCs. The glial scar is essential to keep these factors isolated in the acute phase of disease, and abolishing it is adverse to recovery, while modulation of the glial scar in the chronic phase of disease may stimulate remyelination in white matter disorders. Astrocytes in neuroinflammation The NF-κB pathway is a major inflammatory pathway involved in activation of the innate and adaptive immune responses essential for e.g. generation of T-cell and B-cells. The pathway is constitutively active in many inflammatory disorders of the white matter89,133. In vitro, astrocytes upregulate NF-κB in response to pro-inflammatory cytokines such as IL-17, IL1β, and TNF-α89,134. In vivo, overexpression of the NF-κB inhibitor IκBα in astrocytes results in protection of oligodendrocytes via reduced leukocyte infiltration and lower levels of chemokines during EAE135. NF-κB is also relevant in other CNS disorders that are not classically seen as white matter disorders, including AD, where amyloid-β plaques induce NF-κB activation in an astrocyte-specific manner136. In SOD1 mice, a mouse model of ALS, astrocytic NF-κB promotes degeneration of motor neurons and accelerates disease progression137. Subtle white matter changes are found in neurodegenerative diseases as early as pre-clinical AD where the NF-κB pathway could play a role in exacerbating inflammatory signaling138. Intervention in this pathway is effective, as demonstrated by the MS drug laquinimod, which inhibits astrocytic NF-κB expression4,133. NF-κB signalling represents an important inflammatory pathway in various neurological disorders that is frequently used by astrocytes to exacerbate inflammation. Alleviation of oligodendrocyte pathology via astrocytic NF-κB targeting may be relevant in more white matter disorders, and its use in MS treatment is proof of concept for the relevance of cross-talk in white matter disease therapy. Excitotoxicity Oligodendrocytes are sensitive to excitotoxic damage due to their expression of α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors. In EAE, treatment with AMPA and kainate antagonists significantly reduces oligodendrocyte death and disease severity, suggesting a role for excitotoxic cell death in MS25,139. Moreover, TNF-α triggers astrocytic upregulation of prostaglandin-E2 in vitro, which induces release of glutamate into the extracellular space140, indicating that neuroinflammation exacerbates excitotoxic damage, leading to oligodendrocyte death. Excitotoxicity is further facilitated by downregulation of EAATs, which occurs in the senile plaques in AD, and in ALS128,136. Excitotoxicity in oligodendrocytes is not just glutamate-mediated, but also ATP-mediated, via overstimulation of the P2X purinoreceptor-7 (P2X7) ATP receptors. Similar to the AMPA and kainate receptors, the P2X7 receptor is Ca2+ permeable, and the intracellular Ca2+ damages oligodendrocytes. Studies by Matute and colleagues show that in mice P2X7 antagonists prevent ATP toxicity in oligodendrocytes 7. P2X7 receptors are significantly increased in oligodendrocytes in the optic nerves of people with MS compared to healthy controls, indicating that ATP toxicity might be a relevant pathogenic mechanism in disease141. ATP toxicity is also pathogenic after SCI, increasing demyelination and neuronal death after injury142. In support of this, treatment of rats with P2X7 antagonists increases neuronal survival and functional recovery after SCI142. Stimulation of the P2X7 receptor of neonatal rat-derived astrocytes results in
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