Increased Pan-Type, A1-Type, and A2-Type Astrocyte Activation and Upstream Inflammatory Markers Are Induced by the P2X7 Receptor

Author:

Campagno Keith E.1ORCID,Sripinun Puttipong2ORCID,See Lily P.3ORCID,Li Jiaqi4ORCID,Lu Wennan1,Jassim Assraa Hassan1,Más Gómez Néstor1,Mitchell Claire H.5ORCID

Affiliation:

1. Department of Basic and Translational Science, University of Pennsylvania, Philadelphia, PA 19104, USA

2. Department of Orthodontics, University of Pennsylvania, Philadelphia, PA 19104, USA

3. Department of Endodontics, University of Pennsylvania, Philadelphia, PA 19104, USA

4. Department of Chemistry, Department of Basic and Translational Science, University of Pennsylvania, Philadelphia, PA 19104, USA

5. Department of Basic and Translational Science, Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA

Abstract

This study asked whether the P2X7 receptor was necessary and sufficient to trigger astrocyte polarization into neuroinflammatory activation states. Intravitreal injection of agonist BzATP increased gene expression of pan-astrocyte activation markers Gfap, Steap4, and Vim and A1-type astrocyte activation markers C3, Serping1, and H2T23, but also the Cd14 and Ptx3 genes usually associated with the A2-type astrocyte activation state and Tnfa, IL1a, and C1qa, assumed to be upstream of astrocyte activation in microglia. Correlation analysis of gene expression suggested the P2X7 receptor induced a mixed A1/A2-astrocyte activation state, although A1-state genes like C3 increased the most. A similar pattern of mixed glial activation genes occurred one day after intraocular pressure (IOP) was elevated in wild-type mice, but not in P2X7-/- mice, suggesting the P2X7 receptor is necessary for the glial activation that accompanies IOP elevation. In summary, this study suggests stimulation of the P2X7R is necessary and sufficient to trigger the astrocyte activation in the retina following IOP elevation, with a rise in markers for pan-, A1-, and A2-type astrocyte activation. The P2X7 receptor is expressed on microglia, optic nerve head astrocytes, and retinal ganglion cells (RGCs) in the retina, and can be stimulated by the mechanosensitive release of ATP that accompanies IOP elevation. Whether the P2X7 receptor connects this mechanosensitive ATP release to microglial and astrocyte polarization in glaucoma remains to be determined.

Funder

CHM

KEC

AHJ

Publisher

MDPI AG

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