Transgenic expression of HuR increases vasogenic edema and impedes functional recovery in rodent ischemic stroke

Ardelt, Agnieszka; Carpenter, Randall S.; Iwuchukwu, Ifeanyi; Zhang, An; Lin, Woei; Kościuczuk, Ewa M.; Hinkson, Cyrus L.; Rebeiz, Tania; Reitz, Sydney J.; King, Peter H.

doi:10.1016/j.neulet.2017.09.062

Cited by 6 publications

(9 citation statements)

References 35 publications

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“…This signature encompasses major components of the inflammatory cascade in many CNS diseases. Our work has further demonstrated that glial HuR can impact CNS disease including spinal cord injury (SCI), stroke, glioblastoma, multiple sclerosis, and amyotrophic lateral sclerosis (Ardelt et al, 2017; Kwan et al, 2017a; Kwan et al, 2017b; Matsye et al, 2017; Wang et al, 2019b; Wheeler et al, 2012). On the one hand, genetic deletion of HuR in microglia attenuates glioblastoma growth through an alteration of the tumor immune microenvironment.…”

Section: Introductionmentioning

confidence: 78%

“…For BV2 cells the N/C ratio was similarly reversed with SRI‐42127 treatment (from 0.4 to 1.5) which was similar to unstimulated conditions (N/C ratio of 1.3). Since hypoxia/ischemia induces HuR activation and translocation (Ardelt et al, 2017; Levy et al, 1998; Schultz et al, 2020), we assessed the effect of SRI‐42127 in preventing cytoplasmic accumulation of HuR in PMG under hypoxic (1% O 2 ) conditions (Figure S4). We observed a 50% increase in cytoplasmic HuR under hypoxic conditions compared to normoxia which was blunted by SRI‐42127 by ~70% with SRI‐42127 treatment.…”

Section: Resultsmentioning

confidence: 99%

“…On the one hand, genetic deletion of HuR in microglia attenuates glioblastoma growth through an alteration of the tumor immune microenvironment. On the other hand, transgenic overexpression of HuR in astroglia increases vasogenic edema in acute stroke and SCI, worsens outcome in the former and neuronal loss in the latter (Ardelt et al, 2017; Kwan et al, 2017b; Wang et al, 2019b). This background provides a strong rationale for targeting HuR therapeutically where secondary inflammatory responses accelerate tissue injury or disease progression.…”

Section: Introductionmentioning

confidence: 99%

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SRI‐42127, a novel small molecule inhibitor of the RNA regulator HuR, potently attenuates glial activation in a model of lipopolysaccharide‐induced neuroinflammation

Chellappan

Guha

et al. 2021

Glia

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Glial activation with the production of pro‐inflammatory mediators is a major driver of disease progression in neurological processes ranging from acute traumatic injury to chronic neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. Posttranscriptional regulation is a major gateway for glial activation as many mRNAs encoding pro‐inflammatory mediators contain adenine‐ and uridine‐rich elements (ARE) in the 3′ untranslated region which govern their expression. We have previously shown that HuR, an RNA regulator that binds to AREs, plays a major positive role in regulating inflammatory cytokine production in glia. HuR is predominantly nuclear in localization but translocates to the cytoplasm to exert a positive regulatory effect on RNA stability and translational efficiency. Homodimerization of HuR is necessary for translocation and we have developed a small molecule inhibitor, SRI‐42127, that blocks this process. Here we show that SRI‐42127 suppressed HuR translocation in LPS‐activated glia in vitro and in vivo and significantly attenuated the production of pro‐inflammatory mediators including IL1β, IL‐6, TNF‐α, iNOS, CXCL1, and CCL2. Cytokines typically associated with anti‐inflammatory effects including TGF‐β1, IL‐10, YM1, and Arg1 were either unaffected or minimally affected. SRI‐42127 suppressed microglial activation in vivo and attenuated the recruitment/chemotaxis of neutrophils and monocytes. RNA kinetic studies and luciferase studies indicated that SRI‐42127 has inhibitory effects both on mRNA stability and gene promoter activation. In summary, our findings underscore HuR's critical role in promoting glial activation and the potential for SRI‐42127 and other HuR inhibitors for treating neurological diseases driven by this activation.

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Section: Introductionmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SRI‐42127, a novel small molecule inhibitor of the RNA regulator HuR, potently attenuates glial activation in a model of lipopolysaccharide‐induced neuroinflammation

Chellappan

Guha

et al. 2021

Glia

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“…Thereby, the binding stabilizes TNF‐α mRNA, IL‐6 mRNA, CXCL‐1 mRNA and ICAM‐1 mRNA to amplify the inflammatory effects 41,42,109 . HuR was reported to increase significantly in brain tissue of mice with ischaemia–reperfusion injury after tMCAO 110 …”

Section: Regulation Of Il‐17r Signalling After Strokementioning

confidence: 99%

Interleukin‐17 and ischaemic stroke

et al. 2020

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SummaryInterleukin‐17 (IL‐17) is a cytokine family that includes 6 members, IL‐17A through IL‐17F, most of them are reported to have pro‐inflammatory role. Through binding to their receptors (IL‐17Rs), IL‐17 activates the intracellular signalling pathways to play an important role in autoimmune diseases, including rheumatoid arthritis (RA) and multiple sclerosis (MS). Ischaemic stroke is a complex pathophysiological process mainly caused by regional cerebral ischaemia. Inflammatory factors contribute to the physiological process of stroke that leads to poor prognosis. IL‐17 plays a crucial role in promoting inflammatory response and inducing secondary injury in post‐stroke. Though immune cells and inflammatory factors have been reported to be involved in the damage of stroke, the functions of IL‐17 in this process need to be elucidated. This review focuses on the pathological modulation and the mechanism of IL‐17 family in ischaemic stroke and seeking to provide new insights for future therapies.

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“…In this context, many RBPs are reportedly associated with a poor prognosis of gliomas (Shao et al, 2013 ; Barbagallo et al, 2018 ; Lan et al, 2020 ). In IS, several RBPs participate in the development and influence the prognoses of these patients by promoting inflammatory reactions (Zhou et al, 2014 ; Sharma et al, 2021 ), increasing cerebrovascular permeability, promoting vasogenic cerebral edema (Ardelt et al, 2017 ), regulating apoptosis (Si et al, 2020 ; Zhang et al, 2020 ), and protecting neurons (Fang et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of a 6-RBP gene signature for a comprehensive analysis of glioma and ischemic stroke: Cognitive impairment and aging-related hypoxic stress

Lin

Wang

Chen

et al. 2022

Front. Aging Neurosci.

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There is mounting evidence that ischemic cerebral infarction contributes to vascular cognitive impairment and dementia in elderly. Ischemic stroke and glioma are two majorly fatal diseases worldwide, which promote each other's development based on some common underlying mechanisms. As a post-transcriptional regulatory protein, RNA-binding protein is important in the development of a tumor and ischemic stroke (IS). The purpose of this study was to search for a group of RNA-binding protein (RBP) gene markers related to the prognosis of glioma and the occurrence of IS, and elucidate their underlying mechanisms in glioma and IS. First, a 6-RBP (POLR2F, DYNC1H1, SMAD9, TRIM21, BRCA1, and ERI1) gene signature (RBPS) showing an independent overall survival prognostic prediction was identified using the transcriptome data from TCGA-glioma cohort (n = 677); following which, it was independently verified in the CGGA-glioma cohort (n = 970). A nomogram, including RBPS, 1p19q codeletion, radiotherapy, chemotherapy, grade, and age, was established to predict the overall survival of patients with glioma, convenient for further clinical transformation. In addition, an automatic machine learning classification model based on radiomics features from MRI was developed to stratify according to the RBPS risk. The RBPS was associated with immunosuppression, energy metabolism, and tumor growth of gliomas. Subsequently, the six RBP genes from blood samples showed good classification performance for IS diagnosis (AUC = 0.95, 95% CI: 0.902–0.997). The RBPS was associated with hypoxic responses, angiogenesis, and increased coagulation in IS. Upregulation of SMAD9 was associated with dementia, while downregulation of POLR2F was associated with aging-related hypoxic stress. Irf5/Trim21 in microglia and Taf7/Trim21 in pericytes from the mouse cerebral cortex were identified as RBPS-related molecules in each cell type under hypoxic conditions. The RBPS is expected to serve as a novel biomarker for studying the common mechanisms underlying glioma and IS.

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Transgenic expression of HuR increases vasogenic edema and impedes functional recovery in rodent ischemic stroke

Cited by 6 publications

References 35 publications

SRI‐42127, a novel small molecule inhibitor of the RNA regulator HuR, potently attenuates glial activation in a model of lipopolysaccharide‐induced neuroinflammation

SRI‐42127, a novel small molecule inhibitor of the RNA regulator HuR, potently attenuates glial activation in a model of lipopolysaccharide‐induced neuroinflammation

Interleukin‐17 and ischaemic stroke

Identification of a 6-RBP gene signature for a comprehensive analysis of glioma and ischemic stroke: Cognitive impairment and aging-related hypoxic stress

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