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P2Y2 receptor mediates dying cell removal via inflammatory activated microglia

Izumi Hide1, Hiroko Shiraki1, Akihiro Masuda1

  • 1Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.

Journal of Pharmacological Sciences
|July 31, 2023
PubMed

Insights

Inflammatory microglia remove dying cells via P2Y2 receptors, which upregulate the Axl receptor. This mechanism is crucial for understanding microglial function in the central nervous system (CNS).

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Microglia are crucial for CNS homeostasis, clearing dying cells.
  • Dysfunctional microglial clearance contributes to neurodegeneration in pathological conditions.
  • Mechanisms of dying cell removal by inflammatory microglia are not fully understood.

Purpose of the Study:

  • To investigate the purinergic regulation of dying cell removal by inflammatory microglia.
  • To elucidate the role of P2Y2 receptors in microglial phagocytosis.

Main Methods:

  • Live imaging of primary rat microglia.
  • Lipopolysaccharide (LPS) stimulation to induce microglial activation and cell death.
  • Pharmacological inhibition of P2 receptors using suramin and AR-C118925.
  • Analysis of P2Y2 receptor and Axl expression via mRNA and cell surface localization.
  • Assessment of downstream signaling pathways involving proline-rich tyrosine kinase (Pyk2).

Main Results:

  • LPS-stimulated microglia actively removed dying cells.
  • P2 receptor antagonists (suramin, AR-C118925) inhibited dying cell removal, particularly in LPS-stimulated microglia.
  • LPS induced P2Y2 receptor translocation to the plasma membrane and increased its mRNA expression.
  • LPS upregulated the phagocytic receptor Axl, an effect dependent on P2Y2 receptor and Pyk2 signaling.

Conclusions:

  • Inflammatory stimuli activate P2Y2 receptors in microglia.
  • P2Y2 receptor activation mediates dying cell removal, partly by upregulating the Axl receptor.
  • This purinergic signaling pathway is a key mechanism in inflammatory microglial phagocytosis.
Keywords:
Dying cell removalInflammationLipopolysaccharideMicrogliaP2Y(2) receptor

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