USP18 is a key regulator of immune function in mouse midbrain microglia

Ubiquitin-specific peptidase 18 (USP18) is an important member of the deubiquitinating enzyme family, which has received much attention in recent years for its role in microglia regulation. The aim of this study was to investigate the role of USP18 in midbrain and its potential molecular mechanisms.

In this study, we assessed behavioural phenotypes and pathological changes by adeno-associated virus (AAV)-mediated midbrain-specific USP18 high-expression mouse model. RNA sequencing and untargeted metabolomics were used for multi-omics analysis, and protein expression was detected by Western blot, and ELISA was used to detect neuroinflammatory factor levels.

Our analyses suggest that USP18 is a key regulator of immune activity in the midbrain. USP18 helps maintain the resting state of microglia and exerts neuroprotective effects by promoting TH protein expression. In the midbrain, interference with USP18 expression resulted in significant changes in neuroimmune responses, gene expression associated with inflammation, and metabolite levels. Notably, the TLR signalling pathway was significantly enriched. Loss of USP18 led to a significant increase in the expression of TLR2, Iba-1, and GFAP proteins and a significant decrease in TH levels, and this change was particularly pronounced in microglia. Importantly, the changes observed in USP18 silencing were also reflected in brain tissues of human neurodegenerative diseases.

This study reveals the critical role of USP18 in midbrain and microglia, and suggests it can finely regulate neuroinflammatory and immune responses by modulating TLR2 protein levels. The findings provide new ideas for understanding mechanisms of neurodegenerative diseases and developing therapeutic strategies.