NLRP3 inflammasome priming and activation is involved in depression: A systematic review and meta-analysis

Depression is characterised by a low mood, loss of interest or pleasure, pessimism, impaired concentration, decreased energy, and fatigue. A strong relationship between inflammatory processes and the pathophysiology of depression had been identified. Studies have suggested that the NLRP3 inflammasome is a key contributor to the pathogenesis of depression. This systematic review aimed to synthesise evidence from animal models of depression to evaluate both priming and activation of the inflammasome, with a specific focus on clarifying the role in depressive pathology. PubMed, Scopus, Web of Science, EMBASE and Medline were searched up until November 2024. Studies involving animal models of depression, measuring NLRP3 inflammasome components (NLRP3, ASC, Caspase-1 and IL-1β) were eligible for inclusion. Risk of bias was assessed using SYRCLEs Risk of Bias tool, and random-effects meta-analysis was conducted for each inflammasome component using RevMan. A total of 3345 studies were identified, with 23 accepted after full text screening, and 16 included in the meta-analysis. Across 170 animals (85 depression model, 85 controls), protein and mRNA levels of NLRP3, ASC, Caspase-1, and IL-1β were significantly upregulated in depression models compared to controls. Analysed brain regions included the hippocampus and prefrontal cortex. Moderate heterogeneity was observed between studies (I 2 = 0-68%). This systematic review and meta-analysis demonstrates consistent upregulation of NLRP3 inflammasome components in animal models of depression, therefore suggesting an association with depression. Further research should investigate the therapeutic potential of targeting the NLRP3 inflammasome to reduce neuroinflammation and alleviate depression symptoms in both animal and human studies.