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Methamphetamine-mediated astrocytic pyroptosis and neuroinflammation involves miR-152-NLRP6 inflammasome signaling
Abiola Oladapo1, Muthukumar Kannan1, Uma Maheswari Deshetty1
1Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.
Abstract:
Methamphetamine is a widely abused drug associated with significant neuroinflammation and neurodegeneration, mainly through the activation of glial cells and neurons in the central nervous system. This study investigates the role of the astrocyte-specific NOD-like receptor family pyrin domain-containing protein 6 (NLRP6) inflammasome in methamphetamine-induced astrocytic pyroptosis and neuroinflammation. Our findings demonstrate that methamphetamine exposure induces NLRP6-dependent pyroptosis, astrocyte activation, and the release of proinflammatory cytokines in mouse primary astrocytes. Gene silencing of NLRP6 reduces methamphetamine-induced pyroptosis and proinflammatory cytokines release. We also identified miR-152 as a critical upstream regulator of NLRP6, which is downregulated in methamphetamine-exposed astrocytes. Overexpression of miR-152 decreases NLRP6 expression, mitigating methamphetamine-induced pyroptosis and inflammation. In vivo and ex vivo studies in methamphetamine-exposed mice confirmed these results and showed that methamphetamine induces anxiety-like, cognitive impairment, and depression-like behavior, further linking astrocyte-specific NLRP6 signaling to methamphetamine-induced neuroinflammation. This study highlights the potential of targeting the NLRP6 inflammasome in astrocytes as a therapeutic approach to alleviate methamphetamine-induced central nervous system pathology. Further research is warranted to explore clinical applications and identify therapeutic targets for methamphetamine-related neurological disorders.
Insights
Methamphetamine triggers brain inflammation and cell death by activating astrocyte NLRP6 inflammasomes. Inhibiting this pathway, particularly miR-152, may offer new treatments for methamphetamine-induced neurotoxicity and behavioral issues.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Methamphetamine abuse causes neuroinflammation and neurodegeneration.
- Glial cells, including astrocytes, play a key role in methamphetamine's central nervous system effects.
Purpose of the Study:
- To investigate the role of the astrocyte-specific NOD-like receptor family pyrin domain-containing protein 6 (NLRP6) inflammasome in methamphetamine-induced neuroinflammation and pyroptosis.
- To identify upstream regulators of NLRP6 in methamphetamine-exposed astrocytes.
Main Methods:
- Primary mouse astrocyte cultures and in vivo/ex vivo methamphetamine-exposed mouse models.
- Assessment of NLRP6 inflammasome activation, pyroptosis, cytokine release, and behavioral changes.
- Gene silencing and overexpression techniques for NLRP6 and miR-152.
Main Results:
- Methamphetamine exposure induced NLRP6-dependent astrocytic pyroptosis and proinflammatory cytokine release.
- NLRP6 gene silencing reduced methamphetamine-induced pyroptosis and inflammation.
- miR-152 was downregulated in methamphetamine-exposed astrocytes and acts as an upstream regulator, with its overexpression mitigating NLRP6-induced effects.
- In vivo studies confirmed NLRP6's role in methamphetamine-induced neuroinflammation and associated behavioral deficits (anxiety, cognitive impairment, depression).
Conclusions:
- Astrocyte-specific NLRP6 inflammasome signaling is crucial in methamphetamine-induced neuroinflammation and neurotoxicity.
- miR-152 acts as a key negative regulator of NLRP6 in this context.
- Targeting the astrocyte NLRP6 inflammasome presents a potential therapeutic strategy for methamphetamine-related central nervous system disorders.
