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


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)-1?, resulting in neurotoxic activity. To test this hypothesis, we studied the effects of Meth on IL-1? 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-1? 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-1? 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.

SUBMITTER: Xu E 

PROVIDER: S-EPMC6430126 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Xu Enquan E   Liu Jianuo J   Liu Han H   Wang Xiaobei X   Xiong Huangui H  

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 20180228 2


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  ...[more]

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