Department of Pharmacology, School of Basic Medical Sciences, and Key Laboratory of Anti-Inflammatory and Immunopharmacology, Anhui Medical University, Hefei, 230032, People's Republic of China.
Department of Pharmacy, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, 215008, People's Republic of China.
Inflammation. 2022 Dec;45(6):2172-2185. doi: 10.1007/s10753-022-01683-4. Epub 2022 Jul 2.
NLRP1 inflammasome has been reported to participate in many neurological disorders. Our previous study has demonstrated that NLRP1 inflammasome is implicated in chronic stress-induced depressive-like behaviors in mice. Age has been reported to be related to depression. Here we examine whether NLRP1 inflammasome is involved in the effect of age on depressive disorder. Two chronic stress stimuli, chronic social defeat stress (CSDS) and repeat social defeat stress (RSDS), were used to establish a depression model in mice of different ages. We found that aged mice exhibited worse depressive-like behaviors and locomotor activity compared to young mice. Interestingly, the expression of hippocampal NLRP1 inflammasome complexes and the levels of the inflammatory cytokines were increased in an age-dependent manner. Also, chronic stress-induced increase in the expression of the hippocampal chemokine C-X-C motif ligand 1 (CXCL1), and its cognate receptor, CXC-motif receptor 2 (CXCR2), was more remarkable in aged mice than that in young mice. Moreover, aged mice exhibited lower hippocampal BDNF levels compared to young mice. Hippocampal Nlrp1a knockdown reduced the levels of pro-inflammatory cytokines and the expression of CXCL1/CXCR2, restored BDNF levels, and alleviated chronic stress-induced depressive-like behaviors in aged mice. Our results suggest that NLRP1 inflammasome-CXCL1/CXCR2-BDNF signaling contributes to the effect of age on chronic stress-induced depressive-like behavior in mice.
NLRP1 炎性小体已被报道参与多种神经退行性疾病。我们之前的研究表明，NLRP1 炎性小体参与慢性应激诱导的小鼠抑郁样行为。年龄与抑郁有关。在这里，我们研究 NLRP1 炎性小体是否参与年龄对抑郁障碍的影响。使用两种慢性应激刺激，慢性社交挫败应激（CSDS）和重复社交挫败应激（RSDS），在不同年龄的小鼠中建立抑郁模型。我们发现，与年轻小鼠相比，老年小鼠表现出更严重的抑郁样行为和运动活性。有趣的是，海马 NLRP1 炎性小体复合物的表达和炎症细胞因子的水平呈年龄依赖性增加。此外，慢性应激诱导的海马趋化因子 C-X-C 基序配体 1（CXCL1）及其同源受体 CXC 基序受体 2（CXCR2）的表达在老年小鼠中比在年轻小鼠中更为显著。此外，老年小鼠的海马脑源性神经营养因子（BDNF）水平低于年轻小鼠。海马 Nlrp1a 敲低降低了促炎细胞因子的水平和 CXCL1/CXCR2 的表达，恢复了 BDNF 水平，并缓解了老年小鼠慢性应激诱导的抑郁样行为。我们的研究结果表明，NLRP1 炎性小体-CXCL1/CXCR2-BDNF 信号通路参与年龄对慢性应激诱导的小鼠抑郁样行为的影响。
