report Lysosomal dysfunction is associated with NLRP3 inflammasome activation in chronic unpredictable mild stress-induced depressive mice

NLRP3 inflammasome pathway-mediated inflammatory response is closely associated with depression. Increasing attention has been recently paid to the links between autophagy and depression, however, the rela-tionship between autophagy and NLRP3 inflammasome in depressive behavior remain poorly understood. In the present study, the potential roles of autophagy-lysosome pathway in NLRP3 inflammasome regulation were investigated both in vivo (chronic unpredictable mild stress (CUMS)-induced depressive mouse model) and in vitro (LPS-induced cellular model) model. It demonstrated that CUMS induces depressive-like behaviors in mice, accompanied by increased expression of NLRP3 inflammasome and inflammatory responses. Meanwhile, it promoted the autophagosome marker LC3 and autophagic adapter protein p62 accumulation, accompanied by the decrease of lysosomal cathepsins B and D expression in the prefrontal cortex of mice. Notably, a significant colocalization of NLRP3 and LC3 in CUMS mice by immunofluorescence co-staining were observed. For the in vitro study, disrupting the lysosomal function with Baf A1 significantly increased the LPS-induced NLRP3 inflammasome accumulation and pro-inflammatory factors (IL-1 beta and IL-18) production in BV2 cells. Collec-tively, our results suggested that the autophagic process is related to NLRP3 inflammasome activation, and dysfunctional lysosome in autophagy-lysosomal pathway may retard NLRP3 inflammasome degradation, facil-itating the production of pro-inflammatory factors, thereby contributing to depressive behavior in CUMS mice.

Automated summary

This study investigated the potential roles of autophagy-lysosome pathway in regulating NLRP3 inflammasome in depression. The results showed that CUMS-induced depressive mice exhibited increased expression of NLRP3 inflammasome and inflammatory responses, as well as accumulation of autophagy-related markers. Disrupting lysosomal function in vitro also increased NLRP3 inflammasome accumulation and pro-inflammatory factors production. These findings suggest that autophagy is related to NLRP3 inflammasome activation, and dysfunctional lysosomes may contribute to depressive behavior.