Figure 1.

Main extracellular stimuli and intracellular signaling pathways leading to astrocyte reactivity in ND. Dysfunctional neurons, activated microglia, and astrocytes themselves release a wide range of molecules, which bind specific receptors at the astrocyte plasma membrane. These signals activate intracellular pathways such as the JAK/STAT3 pathway (in red), the NF-κB pathway (in orange), the CN/NFAT pathway (in purple), or the MAPK pathway (in green). The JAK/STAT3 pathway is activated by interleukins such as IL-6 or CNTF. Upon cytokine binding, the kinase JAK is activated and STAT3 is recruited to the gp-130 receptor. JAK phosphorylates STAT3, which dimerizes and translocates to the nucleus, where it binds consensus sequences (STAT responsive element, SRE) in the promoter region of its target genes. In astrocytes, the JAK/STAT3 pathway regulates the transcription of gfap, vimentin, and stat3 itself. STAT3 also induces the expression of SOCS3, the endogenous inhibitor of the JAK/STAT3 pathway, which mediates an inhibitory feedback loop. The NF-κB pathway is activated by pro-inflammatory cytokines such as TNFα and IL-1β. The canonical NF-κB pathway involves the activation of the IKK complex by receptor-bound protein kinases, leading to the phosphorylation of IκBα, the master inhibitor of NF-κB. Upon phosphorylation, IκBα is polyubiquinated and targeted to the proteasome for degradation. The NF-κB subunits p50 and p65 then translocate to the nucleus, where they activate the transcription of various target genes such as inducible nitric oxide synthase and cox2. Like the JAK/STAT3 pathway, NF-κB induces the transcription of its own inhibitor, IκBα. The CN/NFAT pathway is activated by cytokines such as TNFα or by glutamate. CN is a Ca²⁺-dependent phosphatase with many regulatory effects on the NF-κB pathway depending on the initial trigger and cellular context. CN also activates NFAT by dephosphorylation. NFAT binds specific promoter sequences and activates the expression of target genes (cox2). The MAPK pathway is activated by growth factors and cytokines which initiate a phosphorylation cascade. Upon activation, ERK1/2, p38 and c-jun also regulate gene transcription through the activation of a specific set of transcription factors (TF). ND are characterized by intracellular and/or extracellular depositions of pathologic proteins (such as Aβ, Tau, and mHtt, which are shown in blue). In ND, pathological proteins can either be endogenously expressed or internalized by astrocytes. They represent “danger associated molecular patterns” that bind specific pattern recognition receptors (PRR) at the membrane or within astrocytes. These abnormal proteins can interfere with intracellular signaling pathways, activating or inhibiting various signaling proteins (represented as lightning, see Section Additional levels of Complexity and Figure 3). The precise molecular mechanisms involved in astrocytes are mostly unknown. These complex signaling cascades strongly affect the astrocyte transcriptome and lead to astrocyte reactivity. Abbreviations: NFAT RE, NFAT responsive element; GF-R, Growth factor receptor; GPCR, G-protein coupled receptor.