Inhibition of activator protein 1 attenuates neuroinflammation and brain injury after experimental intracerebral hemorrhage.

AIMS: Intracerebral hemorrhage (ICH) is a devastating type of stroke without specific treatment. Activator protein 1 (AP-1), as a gene regulator, initiates cytokine expression in response to environmental stimuli. In this study, we investigated the relationship between AP-1 and neuroinflammation-associated brain injury triggered by ICH. METHODS: Intracerebral hemorrhage mice were developed by autologous blood or collagenase infusion. We measured the dynamics of AP-1 in mouse brain tissues during neuroinflammation formation after ICH. The effects of the AP-1 inhibitor SR11302 on brain injury and neuroinflammation as well as the underlying mechanisms were investigated in vivo and in vitro. RESULTS: AP-1 was significantly upregulated in mouse brain tissue as early as 6 hours after ICH, accompanied by elevations in proinflammatory factors, including interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α. Inhibition of AP-1 using SR11302 reduced neurodeficits and brain edema at day 3 after ICH. SR11302 ablated microglial IL-6 and TNF-α production and brain-infiltrating leukocytes in ICH mice. In addition, SR11302 treatment diminished thrombin-induced production of IL-6 and TNF-α in cultured microglia. CONCLUSIONS: Inhibition of AP-1 curbs neuroinflammation and reduces brain injury following ICH.

Shared genes between Alzheimer's disease and ischemic stroke.

AIMS: Although converging evidence from experimental and epidemiological studies indicates Alzheimer's disease (AD) and ischemic stroke (IS) are related, the genetic basis underlying their links is less well characterized. Traditional SNP-based genome-wide association studies (GWAS) have failed to uncover shared susceptibility variants of AD and IS. Therefore, this study was designed to investigate whether pleiotropic genes existed between AD and IS to account for their phenotypic association, although this was not reported in previous studies. METHODS: Taking advantage of large-scale GWAS summary statistics of AD (17,008 AD cases and 37,154 controls) and IS (10,307 IS cases and 19,326 controls), we performed gene-based analysis implemented in VEGAS2 and Fisher's meta-analysis of the set of overlapped genes of nominal significance in both diseases. Subsequently, gene expression analysis in AD- or IS-associated expression datasets was conducted to explore the transcriptional alterations of pleiotropic genes identified. RESULTS: 16 AD-IS pleiotropic genes surpassed the cutoff for Bonferroni-corrected significance. Notably, MS4A4A and TREM2, two established AD-susceptibility genes showed remarkable alterations in the spleens and brains afflicted by IS, respectively. Among the prioritized genes identified by virtue of literature-based knowledge, most are immune-relevant genes (EPHA1, MS4A4A, UBE2L3 and TREM2), implicating crucial roles of the immune system in the pathogenesis of AD and IS. CONCLUSIONS: The observation that AD and IS had shared disease-associated genes offered mechanistic insights into their common pathogenesis, predominantly involving the immune system. More importantly, our findings have important implications for future research directions, which are encouraged to verify the involvement of these candidates in AD and IS and interpret the exact molecular mechanisms of action.

Upregulation of CD74 and its potential association with disease severity in subjects with ischemic stroke.

Macrophage migration inhibitory factor (MIF) is a key cytokine/chemokine in the activation and recruitment of inflammatory T lymphocytes known to exacerbate experimental stroke severity. MIF effects are mediated through its primary cellular receptor, CD74, the MHC class II invariant chain present on all class II expressing cells, including monocytes, macrophages and dendritic cells (DC). We demonstrated previously that partial MHC class II/peptide constructs (pMHC) can effectively treat mice with experimental stroke, in part through their ability to competitively inhibit MIF/CD74 interactions and downstream signaling. However, the role of MIF and CD74 in human ischemic stroke is not yet well established. To evaluate the therapeutic potential for pMHC, we assessed MIF and CD74 expression levels and their association with disease outcome in subjects with ischemic stroke. MIF levels were assessed in blood plasma by ELISA and CD74 expression was quantified by flow cytometry and qRT-PCR in peripheral blood mononuclear cells (PBMCs) obtained from subjects with ischemic stroke and age and sex-matched healthy controls (HC). MIF levels were increased in plasma and the number of CD74+ cells and CD74 mRNA expression levels were significantly increased in PBMC of subjects with ischemic stroke versus HC, mainly on CD4+ T cells, monocytes and DC. Greater increases of CD74+ cells were seen in subjects with cortical vs. subcortical infarcts and the number of CD74+ cells in blood correlated strongly with infarct size and neurological outcomes. However, differences in MIF and CD74 expression were not affected by age, gender or lesion laterality. Increased CD74 expression levels may serve as a useful biomarker for worse stroke severity and predicted outcomes in subjects with ischemic stroke and provide a rationale for potential future treatment with pMHC constructs.