CNS neuroscience & therapeutics · 2023
Folic acid deficiency exacerbates the inflammatory response of astrocytes after ischemia-reperfusion by enhancing the interaction between IL-6 and JAK-1/pSTAT3.
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Cheng Man, Liang Xiaoshan, Shi Linran, Zhang Qiang, Zhang Liwen, Gong Zhongying, Luo Suhui, Wang Xuan, Zhang Xumei
Аннотация
AIM: To demonstrate the role of IL-6 and pSTAT3 in the inflammatory response to cerebral ischemia/reperfusion following folic acid deficiency (FD).
METHODS: The middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in adult male Sprague-Dawley rats in vivo, and cultured primary astrocytes were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to emulate ischemia/reperfusion injury in vitro.
RESULTS: Glial fibrillary acidic protein (GFAP) expression significantly increased in astrocytes of the brain cortex in the MCAO group compared to the SHAM group. Nevertheless, FD did not further promote GFAP expression in astrocytes of rat brain tissue after MCAO. This result was further confirmed in the OGD/R cellular model. In addition, FD did not promote the expressions of TNF-α and IL-1β but raised IL-6 (Peak at 12 h after MCAO) and pSTAT3 (Peak at 24 h after MCAO) levels in the affected cortices of MCAO rats. In the in vitro model, the levels of IL-6 and pSTAT3 in astrocytes were significantly reduced by treatment with Filgotinib (JAK-1 inhibitor) but not AG490 (JAK-2 inhibitor). Moreover, the suppression of IL-6 expression reduced FD-induced increases in pSTAT3 and pJAK-1. In turn, inhibited pSTAT3 expression also depressed the FD-mediated increase in IL-6 expression.
CONCLUSIONS: FD led to the overproduction of IL-6 and subsequently increased pSTAT3 levels via JAK-1 but not JAK-2, which further promoted increased IL-6 expression, thereby exacerbating the inflammatory response of primary astrocytes.
METHODS: The middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in adult male Sprague-Dawley rats in vivo, and cultured primary astrocytes were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to emulate ischemia/reperfusion injury in vitro.
RESULTS: Glial fibrillary acidic protein (GFAP) expression significantly increased in astrocytes of the brain cortex in the MCAO group compared to the SHAM group. Nevertheless, FD did not further promote GFAP expression in astrocytes of rat brain tissue after MCAO. This result was further confirmed in the OGD/R cellular model. In addition, FD did not promote the expressions of TNF-α and IL-1β but raised IL-6 (Peak at 12 h after MCAO) and pSTAT3 (Peak at 24 h after MCAO) levels in the affected cortices of MCAO rats. In the in vitro model, the levels of IL-6 and pSTAT3 in astrocytes were significantly reduced by treatment with Filgotinib (JAK-1 inhibitor) but not AG490 (JAK-2 inhibitor). Moreover, the suppression of IL-6 expression reduced FD-induced increases in pSTAT3 and pJAK-1. In turn, inhibited pSTAT3 expression also depressed the FD-mediated increase in IL-6 expression.
CONCLUSIONS: FD led to the overproduction of IL-6 and subsequently increased pSTAT3 levels via JAK-1 but not JAK-2, which further promoted increased IL-6 expression, thereby exacerbating the inflammatory response of primary astrocytes.