Abstract
In the brain, NLRP3 (Nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin-domain-containing 3) inflammasome is mainly expressed in microglia located in the hippocampus and other mood-regulated regions, which are particularly susceptible to stress. The activation of NLRP3 inflammasome and production of the activation products may contribute to the development of depressive disorder and memory deficits. Indoleamine 2, 3-dioxygenase (IDO) is a key factor mediating inflammation and major depressive disorder (MDD). We here generated NLRP3 and apoptosis-associated speck-like protein containing caspase recruitment domain (ASC)-knockout mice, respectively, to verify the effects of NLRP3 or ASC deficiency on lipopolysaccharide (LPS)-induced depressive-like behaviors, neuroinflammation, and regulation of IDO expression. Furthermore, we treated these mice with the antidepressant clomipramine (CLO) to observe its effect on depressive-like behaviors and the expression of the NLRP3 inflammasome and LPS-induced IDO. We found that intraperitoneal LPS administration led to marked depressive-like behavior and neuroinflammation. NLRP3 or ASC deficiency attenuated LPS-induced depressive-like symptoms and increased IDO gene expression, which was accompanied by inhibition of LPS-induced microglial activation, suggesting that IDO may be a downstream mediator of the NLRP3 inflammasome in inflammation-mediated depressive-like behaviors. Clomipramine administration ameliorated depressive-like behavior in LPS-treated mice by regulating the expression of ASC and IDO. In conclusion, NLRP3 inflammasome is involved in LPS-induced depressive-like behaviors, and that NLRP3 and ASC may play roles in regulating IDO expression in microglia. This may be a potential mechanism for its involvement in MDD. The antidepressant effect of clomipramine may be exerted through the regulation of ASC-mediated expression of IDO.