The critical role of the hippocampal NLRP3 inflammasome in social isolation-induced cognitive impairment in male mice
The critical role of the hippocampal NLRP3 inflammasome in social isolation-induced cognitive impairment in male mice
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海马 NLRP3 炎性体在雄性小鼠社会隔离引起的认知障碍中的关键作用
DOI：
10.1016/j.nlm.2020.107301
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发表时间：
2020-11-01
影响因子：
2.7
通讯作者：
Wan，Wei
中科院分区：
文献类型：
--
作者：
Niu，Lei;Luo，Shi Shi;Wan，Wei
早期生活压力对认知功能产生有害影响，但其发生机制尚不清楚。NLRP 3炎性体介导的炎症反应已经成为慢性应激诱导的认知障碍的主要贡献者。在本研究中，我们发现8周的慢性社会隔离（SI）导致小鼠认知障碍，显著增加海马NLRP 3炎性体的表达。此外，8周SI程序显著增加海马IL-1β和IL-18水平，而血清IL-1β水平无显著变化，提示IL-1β相关CNS炎症的中枢机制。此外，SI小鼠海马中的炎性小胶质细胞和AMPAR表达减少。米诺环素是一种限制小胶质细胞反应的抗生素，先前的研究也表明米诺环素可以阻止脑中应激诱导的促炎细胞因子表达。我们的实验发现，米诺环素改善SI小鼠的认知行为。米诺环素也阻止了海马NLRP 3炎性小体的表达，表明小胶质细胞可能是SI诱导的海马NLRP 3炎性小体激活的主要贡献者。此外，SI小鼠中的改变也通过用NLRP 3抑制剂MCC 950长期治疗而恢复。这些结果表明，小胶质细胞衍生的NLRP 3炎性小体可能主要参与对社会隔离的炎症反应，并且使用MCC 950的特异性NLRP 3炎性小体抑制可能代表早期应激诱导的认知障碍的有希望的治疗方法。
Early life stress exerts detrimental effects on cognitive function, but the mechanism by which this occurs is unknown. The NLRP3 inflammasome-mediated inflammatory response has emerged as a prominent contributor to cognitive impairment induced by chronic stress. In the present study, we showed that 8-week chronic social isolation (SI) led to cognitive impairment in mice, remarkably increasing expression of the hippocampal NLRP3 inflammasome. Furthermore, the 8-week SI procedure significantly increased the levels of hippocampal IL-1β and IL-18 without significant alteration of the level of serum IL-1β, suggesting a central mechanism for IL-1β-related CNS inflammation. Moreover, inflammatory microglial and expression of AMPAR were reduced in the hippocampus of SI mice. Minocycline is an antibiotic that limits microglia responses, and previous study also showed that minocycline could prevent stress-induced pro-inflammatory cytokine expression in the brain. Our experiment found that minocycline improved cognitive behavior in SI mice. Minocycline also prevented expression of the hippocampal NLRP3 inflammasome, indicating that microglia might be the primary contributor to SI-induced hippocampal NLRP3 inflammasome activation. Furthermore, alterations in SI mice were also restored by chronic treatment with the NLRP3 inhibitor MCC950. These results indicate that the microglia-derived NLRP3 inflammasome may be primarily involved in the inflammatory response to social isolation and that specific NLRP3 inflammasome inhibition using MCC950 may represent a promising therapeutic approach for early stress induced cognitive impairment.