Inflammasome Activation by Methamphetamine Potentiates Lipopolysaccharide Stimulation of IL-1β 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)-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.

System xc− in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness

“…Furthermore, CNS-related symptoms such as depression-like hypoactivity and memory disorder may be observed after sepsis even though obvious neuronal death is not detected 7 . In cases with neuronal death or brain tissue necrosis, such as that induced by high dose LPS administration, damage-associated molecular patterns (DAMPs) may play a critical role in the pathogenesis 8,9 . However, in cases without obvious neuronal death, such as mild endotoxin shock induced by low dose LPS, the etiology of neurological and/or psychiatric illness in the post-septic stage has not been explained clearly.…”

Sodium houttuyfonate attenuates neurological defects after traumatic brain injury in mice via inhibiting NLRP3 inflammasomes

“…This leads to NF‐κB translocation into the nucleus and promotion of transcription of target genes, including those for TNF‐α, IL‐1β, and inflammatory cytokines. [ 29 ] Likewise, HMGB1 and ATP caused phosphorylation of NF‐κB p65, and pretreatment with SH dramatically inhibited this activation. [ 30 ] Of strong clinical importance, we have demonstrated that SH suppresses NLRP3 inflammasome formation and activation in microglia through inhibiting the TLR4/NF‐κB signaling pathway.…”

Role of C/EBP-β in Methamphetamine-Mediated Microglial Apoptosis

“…Pro-inflammatory cytokines IL-1β, IL-6, or TNF-α and LPS induced C/EBP-β upregulation in microglia through activation of the mitogen-activated protein kinases (MAPKs) signaling pathway (Ejarque-Ortiz et al, 2007). Furthermore, MA potentiates LPS stimulation of IL-1β production in microglia (Xu E. et al, 2018). We hypothesize that MA induced microglial reaction and secretion pro-inflammatory cytokines to involve in C/EBP-β expression.…”