Abstract
BackgroundMajor 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 is implicated in the development of depression.MethodsAnimal models of depression were established by four different chronic stress stimuli including chronic unpredictable mild stress (CUMS), chronic restrain stress (CRS), chronic social defeat stress (CSDS), and repeat social defeat stress (RSDS). Depressive-like behaviors were determined by sucrose preference test (SPT), forced swim test (FST), tail-suspension test (TST), open-field test (OFT), social interaction test (SIT), and light-dark test (LDT). The expression of NLRP1 inflammasome complexes, BDNF, and CXCL1/CXCR2 were tested by western blot and quantitative real-time PCR. The levels of inflammatory cytokines were tested by enzyme-linked immunosorbent assay (ELISA) kits. Nlrp1a knockdown was performed by an adeno-associated virus (AAV) vector containing Nlrp1a-shRNA-eGFP infusion.ResultsChronic stress stimuli activated hippocampal NLRP1 inflammasome and promoted the release of pro-inflammatory cytokines IL-1β, IL-18, IL-6, and TNF-α in mice. Hippocampal Nlrp1a knockdown prevented NLRP1 inflammasome-driven inflammatory response and ameliorated stress-induced depressive-like behaviors. Also, chronic stress stimuli caused the increase in hippocampal CXCL1/CXCR2 expression and low BDNF levels in mice. Interestingly, Nlrp1a knockdown inhibited the up-regulation of CXCL1/CXCR2 expression and restored BDNF levels in the hippocampus.ConclusionsNLRP1 inflammasome-driven inflammatory response contributes to chronic stress induced depressive-like behaviors and the mechanism may be related to CXCL1/CXCR2/BDNF signaling pathway. Thus, NLRP1 inflammasome could become a potential antidepressant target.
Highlights
Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, and inflammation has been considered crucial components of the pathogenesis of depression
Chronic stress activates hippocampal Nucleotide oligomerization domain-like receptor protein 1 (NLRP1) inflammasome in mice To investigate the role of NLRP1 inflammasome in depression, we first established animal models by four chronic stimuli including chronic unpredictable mild stress (CUMS), chronic restrain stress (CRS), repeat social defeat stress (RSDS), and chronic social defeat stress (CSDS)
Our data showed that stress stimuli significantly increased the protein expression of NLRP1, a caspaseactivating recruitment domain (ASC), and caspase-1 (Fig. 1a–d), and markedly increased the mRNA levels of NLRP1, ASC, and caspase-1 (Fig. 1e–g), indicating NLRP1 inflammasome was activated in stressinduced depression models
Summary
Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, and inflammation has been considered crucial components of the pathogenesis of depression. Major depressive disorder (MDD) is a highly prevalent psychiatric disorder affecting more than 300 million people worldwide that is characterized by depressed mood, ruminative thoughts, anhedonia, cognitive dysfunction, vegetative symptoms, and even a high suicidal tendency [1,2,3,4]. This disorder impairs the quality of life and causes a burden to patients, their families, and society [5, 6]. Inflammation has been considered important components of the pathogenesis of depressive disorders
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