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Published on: February 5, 2018
Zinc-aggravated M1 microglia regulate astrocytic engulfment via P2×7 receptors
Tomoya Hamada1, Takaaki Aratake2, Youichirou Higashi3
1Department of Pediatrics, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan; Department of Pharmacology, Kochi Medical School, Kochi University, Kohasu, Okoh-cho, Nankoku 783-8505, Japan.
Background:
Glial cells such as astrocytes and microglia play an important role in the central nervous system via communication between these glial cells. Activated microglia can exhibit either the inflammatory M1 phenotype or the anti-inflammatory M2 phenotype, which influences astrocytic neuroprotective functions, including engulfment of cell debris. Recently, extracellular zinc has been shown to promote the inflammatory M1 phenotype in microglia through intracellular zinc accumulation and reactive oxygen species (ROS) generation.
Purpose:
Here, we investigated whether the zinc-enhanced inflammatory M1 phenotype of microglia affects the astrocytic engulfing activity.
Methods:
Engulfing activity was assessed in astrocytes treated with microglial-conditioned medium (MCM) from lipopolysaccharide (LPS)-activated or from ZnCl2-pretreated LPS-activated M1 microglia. The effect of zinc on microglia phenotype was also validated using the zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) and the ROS scavenger Trolox.
Results:
Although treatment of astrocytes with LPS showed no significant effect on the engulfing activity, MCM from LPS-induced M1 microglia increased the beads uptake by astrocytes. This increased uptake activity was suppressed when MCM from LPS-induced M1 microglia pretreated with ZnCl2 was applied to astrocytes, which was further abolished by the intracellular zinc chelator TPEN and the ROS scavenger Trolox. In addition, expression of P2×7 receptors (P2×7R) was increased in astrocytes treated with MCM derived from M1 microglia but not in the M1 microglia pretreated with ZnCl2.
Conclusion:
These findings suggest that zinc pre-treatment abolishes the ability of LPS-induced M1 microglia to increase the engulfing activity in astrocytes via alteration of astrocytic P2×7R.
Insights
Extracellular zinc enhances microglia inflammation, reducing astrocyte debris clearance. Zinc chelators and ROS scavengers restore this crucial neuroprotective function by modulating astrocytic P2×7 receptors.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Glial cells, including astrocytes and microglia, are crucial for central nervous system function.
- Microglia exist in inflammatory (M1) and anti-inflammatory (M2) phenotypes, impacting astrocytic neuroprotection.
- Extracellular zinc promotes M1 microglia via intracellular zinc and reactive oxygen species (ROS) generation.
Purpose of the Study:
- To investigate if zinc-enhanced M1 microglia phenotype affects astrocytic engulfing activity.
- To understand the role of zinc in microglia-astrocyte communication and neuroprotection.
Main Methods:
- Astrocytes were treated with conditioned medium from lipopolysaccharide (LPS)-activated M1 microglia, with or without zinc chloride (ZnCl2) pretreatment.
- The effects of zinc were validated using a zinc chelator (TPEN) and a ROS scavenger (Trolox).
- Engulfing activity and P2×7 receptor (P2×7R) expression were assessed.
Main Results:
- LPS-activated M1 microglia conditioned medium increased astrocyte engulfing activity.
- Zinc pretreatment of M1 microglia abolished this effect, which was reversed by TPEN and Trolox.
- Astrocytic P2×7R expression increased with M1 microglia medium but not with zinc-pretreated M1 microglia medium.
Conclusions:
- Zinc pretreatment of M1 microglia impairs their ability to enhance astrocyte engulfing activity.
- This impairment is mediated by alterations in astrocytic P2×7R expression.
- Zinc's role in modulating microglia-astrocyte interactions impacts neuroprotective functions.
