Involvement of NLRP3 inflammasome in methamphetamine-induced microglial activation through miR-143/PUMA axis

Abstract

Nod-like Receptor Protein 3 (NLRP3) inflammasome activation is known to lead to microglia-mediated neuroinflammation. Methamphetamine is known to induce microglial activation. However, whether NLRP3 inflammasome activation contributes to the microglial activation induced by methamphetamine remains elusive. P53-up-regulated modulator of apoptosis (PUMA) is a known apoptosis inducer; however, their role in microglial activation remains poorly understood. Methamphetamine treatment induced NLRP3 inflammasome activation as well microglial activation in animal model. Intriguingly, downregulation of PUMA significantly inhibited the activation of microglia. Methamphetamine treatment increased the expression of PUMA at protein level but not mRNA level. Further study indicated that PUMA expression was regulated at post-transcriptional level by miR-143, which was decreased in methamphetamine-treated cells via the negative transcription factor nuclear factor-kappa B1 (NF-κB1). Using gain- and loss-of-function approaches, we identified a unique role of miR-143/PUMA in mediating microglial activation via regulation of NLRP3 inflammasome activation. These findings provide new insight regarding the specific contributions of the miR-143/PUMA pathway to NLRP3 inflammasome activation in the context of drug abuse.

Keywords: Methamphetamine; Microglial activation; NLRP3; PUMA; miR-143.