Related Experiment Video

Updated: Feb 10, 2026

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
08:55

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

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RIPK3/MLKL-Mediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic

Jiping Yang1,2, Youyi Zhao1,3, Li Zhang1,2

  • 1Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an, Shaanxi, China.

Cerebral Cortex (New York, N.Y. : 1991)
|May 11, 2018
PubMed

Insights

Necrotic brain cells from stroke trigger inflammatory M1 microglia. Blocking programmed necrosis (RIPK3/MLKL) promotes anti-inflammatory M2 microglia, offering neuroprotection via Myd88 signaling.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Cerebral ischemia causes cell death and inflammation, involving microglia/macrophages with dual M1/M2 roles.
  • The influence of necrotic cells on microglia/macrophage polarization in ischemic stroke is poorly understood.

Purpose of the Study:

  • Investigate how necroptosis in neurons affects microglia/macrophage polarization in cerebral ischemia.
  • Elucidate the molecular mechanisms linking necroptosis to immune cell responses and neuroprotection.

Main Methods:

  • Utilized mouse models of cerebral ischemia with genetic ablation of RIPK3 or MLKL.
  • Employed oxygen-glucose deprivation (OGD) on primary neurons and conditioned medium experiments.
  • Analyzed M1/M2 polarization markers, cytokine profiles (IL-18, TNFα, IL-4, IL-10), and Myd88 expression.
  • Assessed neuroprotection by antagonizing Myd88 function.

Main Results:

  • Ischemia induced RIPK3/MLKL-dependent necroptosis in neurons.
  • Ablating RIPK3 or MLKL shifted microglia/macrophages towards M2 polarization.
  • Neuron-derived IL-18 and TNFα promoted M1 polarization, while RIPK3 deficiency led to M2 polarization.
  • Myd88 signaling in microglia/macrophages was upregulated in ischemic conditions and blocking it conferred neuroprotection.

Conclusions:

  • Necroptotic neurons play a significant role in directing M1/M2 polarization of microglia/macrophages in the ischemic brain.
  • The RIPK3/MLKL-Myd88 pathway represents a novel mechanism linking necroptosis to neuroinflammation and neuroprotection in stroke.

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