Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China; Liuyang Traditional Chinese Medicine Hospital, 421001 Liuyang, Hunan, China.
Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China.
Neurobiol Learn Mem. 2020 Nov;175:107301. doi: 10.1016/j.nlm.2020.107301. Epub 2020 Aug 31.
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.
早期生活压力对认知功能有不利影响，但发生这种情况的机制尚不清楚。NLRP3 炎性小体介导的炎症反应已成为慢性应激引起认知障碍的主要原因。在本研究中，我们表明，8 周的慢性社交隔离（SI）导致小鼠认知功能受损，显著增加了海马 NLRP3 炎性小体的表达。此外，8 周的 SI 程序显著增加了海马 IL-1β 和 IL-18 的水平，而血清 IL-1β 水平没有明显改变，这表明了与 IL-1β 相关的中枢神经系统炎症的中枢机制。此外，SI 小鼠海马中的炎性小胶质细胞和 AMPAR 的表达减少。米诺环素是一种限制小胶质细胞反应的抗生素，先前的研究还表明米诺环素可以防止应激诱导的大脑中促炎细胞因子的表达。我们的实验发现米诺环素改善了 SI 小鼠的认知行为。米诺环素还阻止了海马 NLRP3 炎性小体的表达，表明小胶质细胞可能是 SI 诱导的海马 NLRP3 炎性小体激活的主要原因。此外，慢性给予 NLRP3 抑制剂 MCC950 也恢复了 SI 小鼠的改变。这些结果表明，小胶质细胞衍生的 NLRP3 炎性小体可能主要参与社交隔离的炎症反应，并且使用 MCC950 特异性抑制 NLRP3 炎性小体可能是治疗早期应激引起的认知障碍的有前途的方法。
