Proteinase-activated Receptor-1 Antagonist Attenuates Brain Injury via Regulation of FGL2 and TLR4 after Intracerebral Hemorrhage in Mice

Yao, Xiaoying; Song, Yaying; Wang, Ze; Bai, Shuwei; Yu, Hao; Wang, Yishu; Guan, Yangtai

doi:10.1016/j.neuroscience.2022.02.012

Cited by 2 publications

(4 citation statements)

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“…The activation of TLR4 pathway on these two cells has been shown to contribute to BBB leakage in vitro ( 46 , 47 ). Meanwhile, intracerebral injection of TLR4 inhibitor decreased the hyperpermeability of BBB in adult mice exposed to intracerebral hemorrhage, while the opposite result was observed after TLR4 overexpression ( 48 ). More importantly, the change of BBB function by TLR4 alteration in this research was parallel to its change by FGL2, emphasizing the potential role of TLR4-FGL2 interaction in regulating BBB function ( 48 ).…”

Section: Discussionmentioning

confidence: 97%

“…Meanwhile, intracerebral injection of TLR4 inhibitor decreased the hyperpermeability of BBB in adult mice exposed to intracerebral hemorrhage, while the opposite result was observed after TLR4 overexpression ( 48 ). More importantly, the change of BBB function by TLR4 alteration in this research was parallel to its change by FGL2, emphasizing the potential role of TLR4-FGL2 interaction in regulating BBB function ( 48 ). In fact, TLR4-FGL2 interaction has been proven to cause the activation of peripheral macrophage by LPS stimulation ( 17 ).…”

Section: Discussionmentioning

confidence: 97%

“…FGL2 knockout in two strains of mice did not affect the brain weight as well as the brain-to-body weight ratio of offspring during the perinatal period ( 19 ). Meanwhile, FGL2 knockdown or overexpression had no effect on the neurological function of control adult mice, whereas FGL2 knockdown could alleviate neurological deficits by intracerebral hemorrhage ( 48 ). Moreover, based on our results of NAF extravasation and TJ protein expression in neonatal mice, endogenous FGL2 had no significant effect on normal BBB formation or function, whereas inducible FGL2 by maternal inflammation dramatically participated in BBB disruption.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, based on our results of NAF extravasation and TJ protein expression in neonatal mice, endogenous FGL2 had no significant effect on normal BBB formation or function, whereas inducible FGL2 by maternal inflammation dramatically participated in BBB disruption. Interestingly, latest research reported that FGL2 overexpression and knockdown had no obvious effect on BBB permeability in control adult mice, but pathological inducible FGL2 remarkably caused BBB hyperpermeability ( 48 ). These data collectively proposed that endogenous FGL2 might manipulate BBB function and CNS homeostasis mainly under pathological states due to its abnormal expression.…”

Section: Discussionmentioning

confidence: 99%

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FGL2 deficiency alleviates maternal inflammation-induced blood-brain barrier damage by blocking PI3K/NF-κB mediated endothelial oxidative stress

et al. 2023

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IntroductionThe impairment of blood-brain barrier (BBB) is one of the key contributors to maternal inflammation induced brain damage in offspring. Our previous studies showed Fibrinogen-like protein 2 (FGL2) deficiency alleviated maternal inflammation induced perinatal brain damage. However, its role in BBB remains undefined.MethodsLipopolysaccharide (LPS) was intraperitoneally injected to dams at Embryonic day 17 to establish maternal inflammation model. FGL2 knockout mice and primary brain microvascular endothelial cells (BMECs) were used for the in-vivo and in-vitro experiments. BBB integrity was assessed by sodium fluorescein extravasation and tight junction (TJ) protein expression. Oxidative stress and the activation of PI3K/NF-κB pathway were evaluated to explore the mechanisms underlying.ResultsUpon maternal inflammation, BBB integrity was remarkedly reduced in neonatal mice. Meanwhile, FGL2 expression was consistently increased in BBB-impaired brain as well as in LPS-treated BMECs. Moreover, FGL2 deficiency attenuated the hyperpermeability of BBB, prevented the decline of TJ proteins, and reduced the cytokine expressions in LPS-exposed pups. Mechanistically, the indicators of oxidative stress, as well as the activation of PI3K/NF-κB pathway, were upregulated after LPS exposure in vivo and in vitro. FGL2 deletion decreased the generation of ROS and NO, reduced the endothelial iNOS and NOX2 expressions, and suppressed the PI3K/NF-κB pathway activation. Besides, inhibition of PI3K by LY294002 decreased the oxidative stress in LPS-treated wild-type BMECs. While, overexpression of PI3K by lentivirus reemerged the induction of NOX2 and iNOS as well as NF-κB activation in FGL2-deleted BMECs.ConclusionOur findings indicate that FGL2 deficiency alleviates the maternal inflammation-induced BBB disruption by inhibiting PI3K/NF-κB mediated oxidative stress in BMECs. Targeting FGL2 may provide a new therapy for prenatal brain damage of offspring.

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