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Adipocyte fatty acid-binding protein exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier.

ABSTRACT: AIMS:Adipocyte fatty acid-binding protein (A-FABP) is an adipokine implicating in various metabolic diseases. Elevated circulating levels of A-FABP correlate positively with poor prognosis in ischaemic stroke (IS) patients. No information is available concerning the role of A-FABP in the pathogenesis of IS. Experiments were designed to determine whether or not A-FABP mediates blood-brain barrier (BBB) disruption, and if so, to explore the molecular mechanisms underlying this deleterious effects. METHODS AND RESULTS:Circulating A-FABP and its cerebral expression were increased in mice after middle cerebral artery occlusion. Genetic deletion and pharmacological inhibition of A-FABP alleviated cerebral ischaemia injury with reduced infarction volume, cerebral oedema, neurological deficits, and neuronal apoptosis; BBB disruption was attenuated and accompanied by reduced degradation of tight junction proteins and induction of matrix metalloproteinases-9 (MMP-9). In patients with acute IS, elevated circulating A-FABP levels positively correlated with those of MMP-9 and cerebral infarct volume. Mechanistically, ischaemia-induced elevation of A-FABP selectively in peripheral blood monocyte-derived macrophages and cerebral resident microglia promoted MMP-9 transactivation by potentiating JNK/c-Jun signalling, enhancing degradation of tight junction proteins and BBB leakage. The detrimental effects of A-FABP were prevented by pharmacological inhibition of MMP-9. CONCLUSION:A-FABP is a key mediator of cerebral ischaemia injury promoting MMP-9-mediated BBB disruption. Inhibition of A-FABP is a potential strategy to improve IS outcome.

SUBMITTER: Liao B

PROVIDER: S-EPMC7556749 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Adipocyte fatty acid-binding protein exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier.

Liao Boya B Geng Leiluo L Zhang Fang F Shu Lingling L Wei Ling L Yeung Patrick K K PKK Lam Karen S L KSL Chung Sookja K SK Chang Junlei J Vanhoutte Paul M PM Xu Aimin A Wang Kai K Hoo Ruby L C RLC

European heart journal 20200901 33

<h4>Aims</h4>Adipocyte fatty acid-binding protein (A-FABP) is an adipokine implicating in various metabolic diseases. Elevated circulating levels of A-FABP correlate positively with poor prognosis in ischaemic stroke (IS) patients. No information is available concerning the role of A-FABP in the pathogenesis of IS. Experiments were designed to determine whether or not A-FABP mediates blood-brain barrier (BBB) disruption, and if so, to explore the molecular mechanisms underlying this deleterious ...[more]

PMID: 32350521

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Project description:Inflammatory stimuli induce immunoresponsive gene 1 expression that in turn catalyses the production of itaconate through diverting cis-aconitate away from the tricarboxylic acid cycle. The immunoregulatory effect of the immunoresponsive gene 1/itaconate axis has been recently documented in lipopolysaccharide-activated mouse and human macrophages. In addition, dimethyl itaconate, an itaconate derivative, was reported to ameliorate disease severity in the animal models of psoriasis and multiple sclerosis. Currently, whether immunoresponsive gene 1/itaconate axis exerts a modulatory effect in ischaemic stroke remains unexplored. In this study, we investigated whether immunoresponsive gene 1 plays a role in modulating ischaemic brain injury. In addition, the molecular mechanism underlying the protective effects of immunoresponsive gene 1 in ischaemic stroke was elucidated. Our results showed that immunoresponsive gene 1 was highly induced in the ischaemic brain following ischaemic injury. Interestingly, we found that IRG1-/- stroke animals exhibited exacerbated brain injury, displayed with enlarged cerebral infarct, compared to wild-type stroke controls. Furthermore, IRG1-/- stroke animals presented aggravated blood-brain barrier disruption, associated with augmented Evans blue leakage and increased immune cell infiltrates in the ischaemic brain. Moreover, IRG1-/- stroke animals displayed elevated microglia activation, demonstrated with increased CD68, CD86 and Iba1 expression. Further analysis revealed that immunoresponsive gene 1 was induced in microglia after ischaemic stroke, and deficiency in immunoresponsive gene 1 resulted in repressed microglial heme oxygenase-1 expression and exacerbated ischaemic brain injury. Notably, the administration of dimethyl itaconate to compensate for the deficiency of immunoresponsive gene 1/itaconate axis led to enhanced microglial heme oxygenase-1 expression, alleviated ischaemic brain injury, improved motor function and decreased mortality in IRG1-/- stroke animals. In summary, we demonstrate for the first time that the induction of immunoresponsive gene 1 in microglia following ischaemic stroke serves as an endogenous protective mechanism to restrain brain injury through heme oxygenase-1 up-regulation. Thus, our findings suggest that targeting immunoresponsive gene 1 may represent a novel therapeutic approach for the treatment of ischaemic stroke.

Dataset Information

Adipocyte fatty acid-binding protein exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier.

Publications

Adipocyte fatty acid-binding protein exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier.

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