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Published on: August 25, 2013
Acid sphingomyelinase activity triggers microparticle release from glial cells
Fabio Bianco1, Cristiana Perrotta, Luisa Novellino
1CNR Institute of Neuroscience and Department of Medical Pharmacology, University of Milano, Milano, Italy.
Abstract:
We have earlier shown that microglia, the immune cells of the CNS, release microparticles from cell plasma membrane after ATP stimulation. These vesicles contain and release IL-1beta, a crucial cytokine in CNS inflammatory events. In this study, we show that microparticles are also released by astrocytes and we get insights into the mechanism of their shedding. We show that, on activation of the ATP receptor P2X7, microparticle shedding is associated with rapid activation of acid sphingomyelinase, which moves to plasma membrane outer leaflet. ATP-induced shedding and IL-1beta release are markedly reduced by the inhibition of acid sphingomyelinase, and completely blocked in glial cultures from acid sphingomyelinase knockout mice. We also show that p38 MAPK cascade is relevant for the whole process, as specific kinase inhibitors strongly reduce acid sphingomyelinase activation, microparticle shedding and IL-1beta release. Our results represent the first demonstration that activation of acid sphingomyelinase is necessary and sufficient for microparticle release from glial cells and define key molecular effectors of microparticle formation and IL-1beta release, thus, opening new strategies for the treatment of neuroinflammatory diseases.
Insights
Glial cells, including astrocytes, release microparticles containing IL-1beta upon ATP stimulation. This shedding is dependent on acid sphingomyelinase activation and the p38 MAPK pathway, offering new therapeutic targets for neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the central nervous system's immune cells, release microparticles containing IL-1beta after ATP stimulation.
- These microparticles play a role in central nervous system inflammatory events.
Purpose of the Study:
- To investigate microparticle release from astrocytes and elucidate the underlying shedding mechanism.
- To identify key molecular players involved in ATP-induced microparticle formation and IL-1beta release from glial cells.
Main Methods:
- Utilized glial cell cultures, including those from acid sphingomyelinase knockout mice.
- Stimulated cells with ATP and assessed microparticle shedding and IL-1beta release.
- Investigated the role of acid sphingomyelinase activation and the p38 MAPK cascade using specific inhibitors.
Main Results:
- Astrocytes, similar to microglia, release microparticles upon ATP stimulation via the P2X7 receptor.
- ATP-induced microparticle shedding and IL-1beta release are dependent on acid sphingomyelinase activation and its translocation to the plasma membrane.
- Inhibition of acid sphingomyelinase or the p38 MAPK pathway significantly reduces microparticle formation and IL-1beta release.
Conclusions:
- Acid sphingomyelinase activation is both necessary and sufficient for microparticle release from glial cells.
- The p38 MAPK cascade is crucial for acid sphingomyelinase activation, microparticle shedding, and IL-1beta release.
- These findings offer novel therapeutic strategies for treating neuroinflammatory diseases by targeting microparticle formation.
