The Role And Mechanism Of NLRP1 Inflammasome In Depression-like Behavior Induced By Chronic Stress In Mice

Background: Major depressive disorder(MDD)is a highly prevalent psychiatric disorder and inflammation has been considered crucial components of the pathogenesis of depression.NLRP1 inflammasome-driven inflammatory response is believed to participate in many neurological disorders.However,it is unclear whether NLRP1 inflammasome implicates in the development of depression.Objectives: To observe the role and possible molecular mechanism of NLRP1 inflammasome in depression-like behavior induced by chronic stress in mice.Method: Chronic unpredictable mild stress(CUMS),chronic social defeat stress(CSDS),repeat social defeat stress(RSD)and chronic restrain stress(CRS)were used to establish depression models in mice.The depressive-like behaviors in mice were evaluated by open field test(OFT),tail suspension test(TST),forced swimming test(FST),social interaction test(SIT),light-dark test(LDT)and sucrose preference test(SPT).The expression of NLRP1,ASC,Caspase-1 and BDNF were detected by western blot.The m RNA levels of NLRP1,ASC,Caspase-1 and chemokines CXCL1,CXCR2 were detected by PCR.The levels of IL-6,IL-18,IL-1? and TNF-? were detected by ELISA.The hippocampal NLRP1 knockdown was performed by an adeno-associated virus(AAV)vector containing Nlrp1a-sh RNA-e GFP infusion.Results: 1.Compared with the control group,chronic stress stimulation led to a significant decrease in the sucrose preference rate of mice.The immobility time in the tail suspension test and the forced swimming test was significantly longer.The total moving distance,the time spent in central zone,the numbers of crossing,the time spent in bright zone and the social interaction rate were also significantly reduced.Also,the expression of inflammasome complex NLRP1,ASC and Caspase1 was significantly increased in hippocampus of all depression model mice,and the level of pro-inflammatory cytokines IL-18,IL-1?,TNF-? and IL-6 was significantly increased.Hippocampal Nlrp1 a knockdown significantly inhibits the activation of NLRP1 inflammome and related inflammatory responses.Compared with the model group,Nlrp1 a knockdown significantly increased the sucrose preference rate,the total movement distance,the numbers of crossing and the time spent in central zone.The immobility time in the tail suspension test and the forced swimming test were significantly reduced,the time spent in bright zone and the social interaction rate were also obviously increased,indicating that Nlrp1 a knockdown ameliorated chronic stress induced depression-like behavior in mice.While control sh RNA had no influence on chronic stress-induced depression-like behavior and the expression of related proteins.2.Chronic stress stimuli increased the expression of hippocampal CXCL1 and CXCR2 in mice,while the expression of brain-derived neurotrophic factor(BDNF)was significantly decreased.Nlrp1 a knockdown inhibited chronic stress-induced up-regulation of CXCL1 and CXCR2 expression,and reversed the down-regulation of BDNF expression in hippocampus.Conclusion: NLRP1 inflammasome mediates chronic stress-induced depression-like behavior in mice,and its mechanism may be related to CXCL1/CXCR2/BDNF signaling pathway.Therefore,NLRP1 inflammasome may be the target of potential antidepressant and inhibition of NLRP1 inflammasome may alleviate chronic stress-induced depression-like behavior.