Dataset Information

Genetic Deletion of Kruppel-Like Factor 11 Aggravates Ischemic Brain Injury.

ABSTRACT: Krüppel-like factors (KLFs) belong to the zinc finger family of transcription factors, and their function in the CNS is largely unexplored. KLF11 is a member of the KLF family, and we have previously demonstrated that peroxisome proliferator-activated receptor gamma-mediated cerebral protection during ischemic insults needs recruitment of KLF11 as its critical coactivator. Here, we sought to determine the role of KLF11 itself in cerebrovascular function and the pathogenesis of ischemic stroke. Transient middle cerebral artery occlusion (MCAO) was performed in KLF11 knockout and wild-type control mice, and brain infarction was analyzed by TTC staining. BBB integrity was assessed by using Evans Blue and TMR-Dextran extravasation assays. KLF11 KO mice exhibited significantly larger brain infarction and poorer neurological outcomes in response to ischemic insults. Genetic deficiency of KLF11 in mice also significantly aggravated ischemia-induced BBB disruption by increasing cerebrovascular permeability and edema. Mechanistically, KLF11 was found to directly regulate IL-6 in the brains of ischemic mice. These findings suggest that KLF11 acts as a novel protective factor in ischemic stroke. Elucidating the functional importance of KLF11 in ischemia may lead us to discover novel pharmacological targets for the development of effective therapies against ischemic stroke.

SUBMITTER: Tang X

PROVIDER: S-EPMC5660934 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Genetic Deletion of Krüppel-Like Factor 11 Aggravates Ischemic Brain Injury.

Tang Xuelian X Liu Kai K Hamblin Milton H MH Xu Yun Y Yin Ke-Jie KJ

Molecular neurobiology 20170429 4

Krüppel-like factors (KLFs) belong to the zinc finger family of transcription factors, and their function in the CNS is largely unexplored. KLF11 is a member of the KLF family, and we have previously demonstrated that peroxisome proliferator-activated receptor gamma-mediated cerebral protection during ischemic insults needs recruitment of KLF11 as its critical coactivator. Here, we sought to determine the role of KLF11 itself in cerebrovascular function and the pathogenesis of ischemic stroke. T ...[more]

PMID: 28456933

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Project description:BackgroundThe long-term functional recovery of traumatic brain injury (TBI) is hampered by pathological events, such as parenchymal neuroinflammation, neuronal death, and white matter injury. Krüppel-like transcription factor 11 (KLF 11) belongs to the zinc finger family of transcription factors and actively participates in various pathophysiological processes in neurological disorders. Up to now, the role and molecular mechanisms of KLF11 in regulating the pathogenesis of brain trauma is poorly understood.MethodsKLF11 knockout (KO) and wild-type (WT) mice were subjected to experimental TBI, and sensorimotor and cognitive functions were evaluated by rotarod, adhesive tape removal, foot fault, water maze, and passive avoidance tests. Brain tissue loss/neuronal death was examined by MAP2 and NeuN immunostaining, and Cresyl violet staining. White matter injury was assessed by Luxol fast blue staining, and also MBP/SMI32 and Caspr/Nav1.6 immunostaining. Activation of cerebral glial cells and infiltration of blood-borne immune cells were detected by GFAP, Iba-1/CD16/32, Iba-1/CD206, Ly-6B, and F4/80 immunostaining. Brian parenchymal inflammatory cytokines were measured with inflammatory array kits.ResultsGenetic deletion of KLF11 worsened brain trauma-induced sensorimotor and cognitive deficits, brain tissue loss and neuronal death, and white matter injury in mice. KLF11 genetic deficiency in mice also accelerated post-trauma astrocytic activation, promoted microglial polarization to a pro-inflammatory phenotype, and increased the infiltration of peripheral neutrophils and macrophages into the brain parenchyma. Mechanistically, loss-of-KLF11 function was found to directly increase the expression of pro-inflammatory cytokines in the brains of TBI mice.ConclusionKLF11 acts as a novel protective factor in TBI. KLF11 genetic deficiency in mice aggravated the neuroinflammatory responses, grey and white matter injury, and impaired long-term sensorimotor and cognitive recovery. Elucidating the functional importance of KLF11 in TBI may lead us to discover novel pharmacological targets for the development of effective therapies against brain trauma.

Project description:Our previous study has shown that the transcription factor Krüppel-like factor 7 (KLF7) promotes peripheral nerve regeneration and motor function recovery after spinal cord injury. KLF7 also participates in traumatic brain injury, but its regulatory mechanisms remain poorly understood. In the present study, an HT22 cell model of traumatic brain injury was established by stretch injury and oxygen-glucose deprivation. These cells were then transfected with an adeno-associated virus carrying KLF7 (AAV-KLF7). The results revealed that, after stretch injury and oxygen-glucose deprivation, KLF7 greatly reduced apoptosis, activated caspase-3 and lactate dehydrogenase, downregulated the expression of the apoptotic markers B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax) and cleaved caspase-3, and increased the expression of βIII-tubulin and the antiapoptotic marker Bcl-2. Furthermore, KLF7 overexpression upregulated Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) phosphorylation in HT22 cells treated by stretch injury and oxygen-glucose deprivation. Immunoprecipitation assays revealed that KLF7 directly participated in the phosphorylation of STAT3. In addition, treatment with AG490, a selective inhibitor of JAK2/STAT3, weakened the protective effects of KLF7. A mouse controlled cortical impact model of traumatic brain injury was then established. At 30 minutes before modeling, AAV-KLF7 was injected into the ipsilateral lateral ventricle. The protein and mRNA levels of KLF7 in the hippocampus were increased at 1 day after injury and recovered to normal levels at 3 days after injury. KLF7 reduced ipsilateral hippocampal atrophy, decreased the injured cortex volume, downregulated Bax and cleaved caspase-3 expression, and increased the number of 5-bromo-2'-deoxyuridine-positive neurons and Bcl-2 protein expression. Moreover, KLF7 transfection greatly enhanced the phosphorylation of JAK2 and STAT3 in the ipsilateral hippocampus. These results suggest that KLF7 may protect hippocampal neurons after traumatic brain injury through activation of the JAK2/STAT3 signaling pathway. The study was approved by the Institutional Review Board of Mudanjiang Medical University, China (approval No. mdjyxy-2018-0012) on March 6, 2018.

Dataset Information

Genetic Deletion of Kruppel-Like Factor 11 Aggravates Ischemic Brain Injury.

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Genetic Deletion of Krüppel-Like Factor 11 Aggravates Ischemic Brain Injury.

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