JAK-STAT Signaling Pathway and Gliosis in Neuroinflammatory Diseases

Transient prenatal ruxolitinib treatment suppresses astrogenesis during development and improves learning and memory in adult mice

“…A strategy to suppress or delay astrogenesis could potentially address the neurogenic-to-gliogenic shifts observed in individuals with Down syndrome 17 , 20 – 22 , Noonan syndrome 19 and disease-related to dysfunctional astrogenesis 10 , 18 . This study demonstrated the transplacental astrogenesis-suppression effect in the developing embryonic mouse brain and how it could lead to lasting effects into young adulthood after ruxolitinib withdrawal.…”

“…When STATs bind to the receptor, the conserved tyrosine residue near the C-terminus is phosphorylated and lead to STATs dimerisation through the conserved SH2 domain. The phosphorylated STAT dimers translocate into the nucleus and bind to the promoter of the target gene to initiate transcriptional activity 10 . Several studies showed that ruxolitinib treated cells, such as pancreatic tumour cells derived from p53-null mice, resulted in p-JAK2 and p-STAT3 suppression 11 .…”

“…During gliogenesis, the STAT3 transcription factor is activated through phosphorylation by JAKs and competitively binds to the p300/CBP coactivator proteins leading to Notch-mediated activation of gliogenic fate that produce astrocytes 17 . Dysfunctional astrocytes due to the impairment of astrocytogenesis have been implicated in various disorders related to the central nervous system (CNS) such as Alzheimer's disease, epilepsy, brain tumour, major depression and Down syndrome (DS) 10 , 18 . Interestingly, a neurogenic-to-gliogenic shift during neurodevelopment has been shown in Down 17 and Noonan syndromes 19 characterised by increased astrogenesis or preferential NPCs differentiation into astrocytes 19 , 20 .…”

The Struggle of Neural Progenitors in Down Syndrome Brain: The Need for Neuromodulation Beyond Symptomatic Mitigations

“…These cytokines are wellknown activators of the JAK-STAT signalling pathway, a neuroinflammation regulatory pathway mediated by upstream interferons or interferons receptors. The extra copy of the IFN receptor and the elevation of IFN level have been postulated to sensitise the cells to interferon interaction and lead to activation of the JAK-STAT signalling pathway in astrocyte as well as microglia (33)(34)(35), turning them from the resting into the reactive form. Activation of glial cells could lead to neuroinflammation via the release of nitric oxide (NO) (36,37).…”