Inflammasome Activation by Methamphetamine Potentiates Lipopolysaccharide Stimulation of IL-1β Production in Microglia

Enquan Xu, Jianuo Liu, Han Liu, Xiaobei Wang, Huangui Xiong

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Methamphetamine (Meth) is an addictive psychostimulant abused worldwide. Ample evidence indicate that chronic abuse of Meth induces neurotoxicity via microglia-associated neuroinflammation and the activated microglia present in both Meth-administered animals and human abusers. The development of anti-neuroinflammation as a therapeutic strategy against Meth dependence promotes research to identify inflammatory pathways that are specifically tied to Meth-induced neurotoxicity. Currently, the exact mechanisms for Meth-induced microglia activation are largely unknown. NLRP3 is a well-studied cytosolic pattern recognition receptor (PRR), which promotes the assembly of the inflammasome in response to the danger-associated molecular patterns (DAMPs). It is our hypothesis that Meth activates NLRP3 inflammasome in microglia and promotes the processing and release of interleukin (IL)-1β, resulting in neurotoxic activity. To test this hypothesis, we studied the effects of Meth on IL-1β maturation and release from rat cortical microglial cultures. Incubation of microglia with physiologically relevant concentrations of Meth after lipopolysaccharide (LPS) priming produced an enhancement on IL-1β maturation and release. Meth treatment potentiated aggregation of inflammasome adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), induced activation of the IL-1β converting enzyme caspase-1 and produced lysosomal and mitochondrial impairment. Blockade of capase-1 activity, lysosomal cathepsin B activity or mitochondrial ROS production by their specific inhibitors reversed the effects of Meth, demonstrating an involvement of inflammasome in Meth-induced microglia activation. Taken together, our results suggest that Meth triggers microglial inflammasome activation in a manner dependent on both mitochondrial and lysosomal danger-signaling pathways.

Original languageEnglish (US)
Pages (from-to)237-253
Number of pages17
JournalJournal of Neuroimmune Pharmacology
Volume13
Issue number2
DOIs
StatePublished - Jun 1 2018

Keywords

  • Il-1β
  • Inflammasome
  • Methamphetamine
  • Microglia
  • NLRP3
  • Neuroinflammation

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

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