Involvement of inflammasome activation in lipopolysaccharide-induced mice depressive-like behaviors

Abstract

Aims: The NLRP3 inflammasome is a cytoplasmic multiprotein complex of the innate immune system that regulates the cleavage of interleukin-1β and interleukin-18 precursors. It can detect a wide range of danger signals and trigger a series of immune-inflammatory reactions. There were plenty of studies indicating that activation of the immune system played pivotal roles in depression. However, the underlying mechanisms of immune-depression interactions remained elusive and there was no report about the involvement of inflammasome activation in depression.

Methods: We established an acute depression mouse model with lipopolysaccharide to explore the involvement of inflammasome activation in depression.

Results: The lipopolysaccharide-treated mice displayed depressive-like behaviors and pro-inflammatory cytokine interleukin-1β protein and mRNA levels significantly increased. The NLRP3 inflammasome mRNA expression level also significantly elevated in depressed mice brain. Pretreatment with the NLRP3 inflammasome inhibitor Ac-YVAD-CMK significantly abrogated the depressive-like behaviors induced by lipopolysaccharide.

Conclusion: These data suggest for the first time that the NLRP3 inflammasome is involved in lipopolysaccharide-induced mice depressive-like behaviors. The NLRP3 inflammasome may be a central mediator between immune activation and depression, which raises the possibility that it may be a more specific target for the depression treatments in the near future.

Keywords: Cytokines; Depression; Inflammation; Interleukin-1β; NLRP3 inflammasome.

Figure 1

Interleukin‐1β protein concentration and mRNA expression level significantly elevated in lipopolysaccharide (LPS)‐treated mice brain. Sucrose preference test (A) and immobility time of forced swim test (B) confirmed depressive‐like behaviors post‐LPS administration. Interleukin‐1β protein concentration (C) and mRNA expression level (D) were analyzed 24 h after LPS injection. Data are represented as mean ± SEM (n = 8–10 in A, B; n = 4–6 in C, D). *P < 0.05, **P < 0.01 and ***P < 0.001 for each comparison.

Figure 2

NLRP3 inflammasome mRNA expression level increased significantly in lipopolysaccharide (LPS)‐treated mice brain. The mRNA expression levels of NLRP3 inflammasome components NLRP3 (A), ASC (B) and caspase‐1 (C) were measured by real‐time RT‐PCR. Data are represented as mean ± SEM (n = 4–6 in each group). *P < 0.05 and **P < 0.01 for each comparison.

Figure 3

NLRP3 inflammasome inhibitor Ac‐YVAD‐CMK significantly ameliorated lipopolysaccharide (LPS)‐induced mice depressive‐like behaviors. There were no significant differences between control group and YVAD group both in sucrose preference test (A) and forced swim test (B), while the LPS group had significant lower sucrose preference and longer immobility time compared with control group and YVAD group. The behavioral changes elicited by LPS were significantly mitigated by the pre‐administration of Ac‐YVAD‐CMK (YVAD + LPS group). Data are represented as mean ± SEM (n = 8–10). *P < 0.05, **P < 0.01 and ***P < 0.001 for each comparison.