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. 2023 Dec 5;24(24):17146. doi: 10.3390/ijms242417146

Figure 2.

Figure 2

Graphical representation of the most important astrocytic roles in BBB and CNS function. (1) Neurovascular unit. ATP from active neurons activates astrocytic P2X receptors that induce PL-D2 and diacylglycerol lipase-mediated production of arahidonic acid and generation of prostaglandin E2. Prostaglandin E2 is secreted by the astrocytic end-feed and induces pericyte relaxation by binding to EP4-R. (2) Apolipoprotein E (ApoE). The astrocytes are the main source of ApoE in the CNS. ApoE-4 activates cyclophilin A (MMP-9) in the pericytes which disrupts the BBB. ApoE3, produced by astrocytes, blocks the APOE-4-associated BBB disruption. (3) Hedgehog Family. Sonic Hedgehog (SHh). SHh signaling through endothelial receptors decreases TNF-alfa, IL-6, and IL-1b transcription factors, increases the expression of TJs (occludin, ZO-1, etc.), and reduces ICAM-1 expression on ECs. Desert Hedgehog (DHh) regulates the binding between astrocytic end-feet and protein-patched receptors (PTCH-R). (4) Astrogliosis. STAT3 activation in reactive astrocytes (via phosphorylation by Janus kinase) leads to reactive astrogliosis. STAT3 regulates the survival of proliferating reactive astrocytes. Additionally, MMP-2 and -9 are released from reactive astrocytes, favoring BBB disruption. Janus kinase-STAT3 inhibition has been shown to reduce levels of IL-6, IL-1b, and IL-4. (5) NF-Kb activation. Astrogliosis is accompanied by NF-kB activation in reactive astrocytes which triggers BBB disruption. The canonical NK-κB pathway is induced by TLRs, pro-inflammatory cytokines, ROS, and NO. The alternative NK-κB pathway is activated by the B cell activating factor of the TNF family (BAFF), lymphotoxin β, and CD40L. NF-kB pathway activation leads to glutamine, ATP, IFNγ, TGF-β, IL-1α, TNFα, and iNOS production, promoting a pro-inflammatory environment and leading to BBB disruption.