Involvement of NLRP6-Dependent Pyroptosis in Methamphetamine-Induced Neuroinflammation

Methamphetamine (Meth) 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. Though, the etiologies of Meth-induced neurotoxicity are numerous, neuroinflammation is a focal point in mediating this pathology. Mounting evidence implicates inflammasome proteins as critical mediators regulating cellular activation, thereby impacting altered homeostasis of several crucial biological processes. While Meth has been shown to change the gene expression profiles of various CNS cells, there is a knowledge gap in our understanding of how Meth mediates the activation of astrocyte-specific NLRP6 (NOD-Iike receptor family, pyrin domain-containing protein 6) that controls cellular activation. This study investigates the role of the astrocyte-specific NOD-like receptor family pyrin domain-containing protein 6 (NLRP6) inflammasome in Meth-induced astrocytic pyroptosis and neuroinflammation. Our findings demonstrate that Meth exposure induces NLRP6-dependent pyroptosis, astrocyte activation, and the release of proinflammatory cytokines in mouse primary astrocytes. Gene silencing of NLRP6 reduces Meth-induced pyroptosis, and proinflammatory cytokines release. We also identified miR-152 as a critical upstream regulator of NLRP6, which is downregulated in Meth-exposed astrocytes. Overexpression of miR-152 decreases NLRP6 expression, mitigating Meth-induced pyroptosis and inflammation. In vivo and ex vivo studies in Meth-exposed mice confirmed these results and showed that Meth induces anxiety-like, cognitive impairment and depression-like behavior, further linking astrocyte-specific NLRP6 signaling to Meth-induced neuroinflammation. This study highlights the potential of targeting the NLRP6 inflammasome in astrocytes as a therapeutic approach to alleviate Meth-induced CNS pathology. Further research is warranted to explore clinical applications and identify therapeutic targets for Meth-related neurological disorders.