Neuronal EphA4 Regulates OGD/R-Induced Apoptosis by Promoting Alternative Activation of Microglia

Wei, Huixing; Yao, Pei-Sen; Chen, Pingping; Guan, Jianhua; Zhuang, Jin-Hong; Zhu, Jiang; Wu, Gang; Yang, Jiajun

doi:10.1007/s10753-018-0914-4

Cited by 16 publications

(15 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have shown that Eph receptor/Ephrin signaling regulates microglia activity in different neuropathological conditions (Deng et al, 2017;Wei et al, 2019). EphB receptor/Ephrin B is the most well-studied signaling in microglia.…”

Section: Introductionmentioning

confidence: 99%

“…EphA receptor signaling may also contribute to microglia activation and proliferation. In the oxygen-glucose deprivation and reperfusion (OGD/R) model to induce ischemic injury, neuronal EphA4 deficiency inhibits microglia proliferation and promotes their polarization into anti-inflammatory phenotype (Wei et al, 2019). Most of the previous studies used ionized calcium-binding adaptor molecule 1 (Iba1) as a microglia marker.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Conditional Deletion of EphA4 on Cx3cr1-Expressing Microglia Fails to Influence Histopathological Outcome and Blood Brain Barrier Disruption Following Brain Injury

Soliman

Mills

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Erythropoietin-producing human hepatocellular receptors play a major role in central nervous system injury. Preclinical and clinical studies revealed the upregulation of erythropoietin-producing human hepatocellular A4 (EphA4) receptors in the brain after acute traumatic brain injury. We have previously reported that Cx3cr1-expressing cells in the peri-lesion show high levels of EphA4 after the induction of controlled cortical impact (CCI) injury in mice. Cx3cr1 is a fractalkine receptor expressed on both resident microglia and peripheral-derived macrophages. The current study aimed to determine the role of microglial-specific EphA4 in CCI-induced damage. We used Cx3cr1CreER/+ knock-in/knock-out mice, which express EYFP in Cx3cr1-positive cells to establish microglia, EphA4-deficient mice following 1-month tamoxifen injection. Consistent with our previous findings, induction of CCI in wild-type (WT) Cx3cr1CreER/+EphA4+/+ mice increased EphA4 expression on EYFP-positive cells in the peri-lesion. To distinguish between peripheral-derived macrophages and resident microglia, we exploited GFP bone marrow-chimeric mice and found that CCI injury increased EphA4 expression in microglia (TMEM119+GFP–) using immunohistochemistry. Using Cx3cr1CreER/+EphA4f/f (KO) mice, we observed that the EphA4 mRNA transcript was undetected in microglia but remained present in whole blood when compared to WT. Finally, we found no difference in lesion volume or blood-brain barrier (BBB) disruption between WT and KO mice at 3 dpi. Our data demonstrate a nonessential role of microglial EphA4 in the acute histopathological outcome in response to CCI.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Conditional Deletion of EphA4 on Cx3cr1-Expressing Microglia Fails to Influence Histopathological Outcome and Blood Brain Barrier Disruption Following Brain Injury

Soliman

Mills

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Neural cells near amyloid plaques and neurofibrillary tangles in patients with AD exhibit increased expression of the EphA4 protein . Besides their impacts on synaptic plasticity, EphA4 and ephrins mediate microglial proliferation, microglial phenotype transition, and inflammatory response modulation via signaling between neurons and microglia . Thus, Rhy may alleviate AD pathology by modulating inflammatory and immune responses in the brain.…”

Section: Results and Discussionmentioning

confidence: 99%

“…34 Besides their impacts on synaptic plasticity, EphA4 and ephrins mediate microglial proliferation, microglial phenotype transition, and inflammatory response modulation via signaling between neurons and microglia. 35 Thus, Rhy may alleviate AD pathology by modulating inflammatory and immune responses in the brain. It is of interest to examine whether Rhy exerts its beneficial effects in AD through EphA4 signaling.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Rhynchophylline Administration Ameliorates Amyloid-β Pathology and Inflammation in an Alzheimer’s Disease Transgenic Mouse Model

Hung

Lau

et al. 2021

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Alzheimer's disease (AD), the most common neurodegenerative disease, has limited treatment options. As such, extensive studies have been conducted to identify novel therapeutic approaches. We previously reported that rhynchophylline (Rhy), a small molecule EphA4 inhibitor, rescues impaired hippocampal synaptic plasticity and cognitive dysfunctions in APP/PS1 mice, an AD transgenic mouse model. To assess whether Rhy can be developed as an alternative treatment for AD, it is important to examine its pharmacokinetics and effects on other disease-associated pathologies. Here, we show that Rhy ameliorates amyloid plaque burden and reduces inflammation in APP/PS1 mice. Transcriptome analysis revealed that Rhy regulates various molecular pathways in APP/PS1 mouse brains associated with amyloid metabolism and inflammation, specifically the ubiquitin proteasome system, angiogenesis, and microglial functional states. These results show that Rhy, which is blood−brain barrier permeable, is beneficial to amyloid pathology and regulates multiple molecular pathways.

show abstract

“…VGF, a neurosecretory protein, is a precursor of a number of cleaved peptides, including TLQP-21, which can promote anti-inflammatory phenotype of microglia (Elmadany et al, 2020 ), thus the decreased abundance of VGF in the INF group may delay the anti-inflammatory microglial response in the developing brain. Besides, decreased levels of EPHA4 may facilitate an anti-inflammatory microglia phenotype, since EphA4 deletion inhibits microglia proliferation and promotes the M2 polarization (Wei et al, 2019 ). Preclinical studies in pigs showed that the microglial response to inflammatory challenges is transient (Muk et al, 2022 ), however the early-life immune activation makes this long-living tissue resident macrophages more sensitive to a secondary inflammatory insult later in life, and may also have long-term behavior impact (Bilbo et al, 2006 ).…”

Section: Discussionmentioning

confidence: 99%

Proteins Involved in Synaptic Plasticity Are Downregulated in the Cerebrospinal Fluid of Infants With Clinical Sepsis Complicated by Neuroinflammation

Jiang

Peng

Pankratova

et al. 2022

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Newborn infants are prone to sepsis and related inflammation of different organs. Neuroinflammation has been associated with long-term adverse neuronal (neuropsychiatric/neurodegenerative) outcomes, including attention deficit hyperactivity disorder (ADHD) or even Alzheimer's disease. Despite a vast number of findings on sepsis-induced inflammatory responses in the central nervous system (CNS), how neuroinflammation affects brain development remains largely elusive. In this study, neonates with clinical sepsis and screened for meningitis were included and classified by the neuroinflammation status based on cerebrospinal fluid (CSF) parameters (INF vs. NOINF). CSF samples collected from clinical screening were subjected to proteomics analysis. Proteins with differential abundance were subjected to enrichment analysis to reveal affected biological pathways. INF and NOINF infants had similar demographic data and hematological and biochemical parameters in blood and CSF. The CSF proteomes were essentially different between the two groups. All 65 proteins with differential abundance showed lower abundance in the INF group and functionally covered pivotal developmental processes, including axonal and synaptic function and extracellular homeostasis. CSF proteins, PTPRZ1 and IGFBP4, were correlated with C-reactive protein (CRP) and ratios of immature/total neutrophils in blood. In general, a substantial change in the CSF protein profile was found under neuroinflammation, and these changes are related to systemic conditions. The results suggest that changes in CSF proteins may be involved in sepsis-affected neurodevelopment, such as disturbances in circuit formation, which has the potential to predispose neonates to long-term adverse outcomes.

show abstract

Neuronal EphA4 Regulates OGD/R-Induced Apoptosis by Promoting Alternative Activation of Microglia

Cited by 16 publications

References 40 publications

Conditional Deletion of EphA4 on Cx3cr1-Expressing Microglia Fails to Influence Histopathological Outcome and Blood Brain Barrier Disruption Following Brain Injury

Conditional Deletion of EphA4 on Cx3cr1-Expressing Microglia Fails to Influence Histopathological Outcome and Blood Brain Barrier Disruption Following Brain Injury

Rhynchophylline Administration Ameliorates Amyloid-β Pathology and Inflammation in an Alzheimer’s Disease Transgenic Mouse Model

Proteins Involved in Synaptic Plasticity Are Downregulated in the Cerebrospinal Fluid of Infants With Clinical Sepsis Complicated by Neuroinflammation

Contact Info

Product

Resources

About