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

Hui-Xing Wei1, Pei-Sen Yao2, Ping-Ping Chen1

  • 1Department of Neurology, The First Affiliated Hospital of Fujian Medical University, 20 Chazhong Road, Fuzhou, 350000, Fujian, People's Republic of China.

Inflammation
|October 27, 2018
PubMed

Insights

Blocking neuronal EphA4 (erythropoietin-producing human hepatocellular carcinoma cell receptor 4) reduces brain injury after ischemia. This approach promotes beneficial M2 microglia activation via RhoA/ROCK2 signaling, offering a potential therapeutic strategy for ischemic stroke.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Post-injury inflammation, driven by activated microglia, exacerbates neuropathology in ischemic injuries.
  • Microglia exist in two states: classically activated (M1) and alternatively activated (M2).
  • Shifting microglia from M1 to M2 dominance is a potential therapeutic strategy for ischemic injury.

Purpose of the Study:

  • To investigate the role of neuronal erythropoietin-producing human hepatocellular carcinoma cell receptor 4 (EphA4) in ischemic brain injury.
  • To determine if modulating EphA4/ephrin signaling impacts microglia polarization and subsequent neuropathology.
  • To elucidate the underlying molecular mechanisms, including RhoA/ROCK2 signaling, involved in EphA4-mediated microglia regulation.

Main Methods:

  • Utilized short hairpin RNA (shRNA) to knockdown neuronal EphA4 in an in vitro model of ischemic injury (oxygen-glucose deprivation and reperfusion - OGD/R).
  • Assessed OGD/R-induced apoptosis and microglia proliferation.
  • Analyzed microglia polarization towards M1 or M2 phenotypes and measured inflammatory mediators, anti-inflammatory cytokines, and neurotrophic factors.
  • Investigated the involvement of RhoA/Rho-associated kinase 2 (ROCK2) signaling pathway.

Main Results:

  • Neuronal EphA4 knockdown significantly attenuated OGD/R-induced apoptosis and microglia proliferation.
  • Knockdown of EphA4 promoted a shift in microglia polarization towards the M2 phenotype.
  • M2-polarized microglia released reduced pro-inflammatory mediators and increased anti-inflammatory cytokines and neurotrophic factors.
  • The protective effects of EphA4 knockdown were mediated through the RhoA/ROCK2 signaling pathway.

Conclusions:

  • Blockage of neuronal EphA4/ephrin signaling mitigates ischemic brain injury.
  • Modulating EphA4 influences microglia polarization, favoring the beneficial M2 phenotype.
  • The EphA4/ephrin pathway regulates microglia activation via the RhoA/ROCK2 signaling cascade, presenting a novel therapeutic target for ischemic stroke.
Keywords:
EphA4/ephrin signalingIschemiaRhoA/ROCK2 signalinginflammatory injurymicroglial polarization

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