a potential for reactive astrocytes to exert detrimental or maladaptive effects through inappropriate gain-of-functions, which might be driven by chronic exposure to reactivity triggers (Key Figure, Figure 2F,G). For example, transgenically-targeted molecular deletion studies show that attenuation of pro-inflammatory signaling mediated by NFkB, VEGFA or Ccl2 in reactive astrocytes, can improve neurological outcome during experimental autoimmune inflammation in transgenic mice [79–81]. Furthermore, mounting evidence shows that chronic astrocyte exposure to reactivity triggers during autoimmune or neurodegenerative disorders, can help drive excessive inflammation [32, 61]. In these contexts, astrocyte reactivity may be regarded in the same light as inflammation, i.e. normal astrocyte reactivity, similarly to normal inflammation, is an adaptive response to CNS injury and disease that can be considered an essential component of CNS innate immunity. However, under certain circumstances, chronic astrocyte reactivity, like chronic inflammation, may benefit from attenuation. From another angle, the opposite may also be true, such that in some cases it may be important to augment pro-inflammatory signaling and attenuate anti-inflammatory signaling by reactive astrocytes. For example, it is well-documented that reactive astrocytes can control and limit the spread of inflammation after traumatic injury, stroke and other conditions, particularly through Stat3-mediated signaling [11, 32, 65]. However,
