Regulation of indoleamine 2, 3‐dioxygenase in hippocampal microglia by NLRP3 inflammasome in lipopolysaccharide‐induced depressive‐like behaviors,European Journal of Neuroscience

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Regulation of indoleamine 2, 3‐dioxygenase in hippocampal microglia by NLRP3 inflammasome in lipopolysaccharide‐induced depressive‐like behaviors
European Journal of Neuroscience ( IF 2.7 ) Pub Date : 2020-10-23 , DOI: 10.1111/ejn.15016
Shanshan Zhang ₁ , Ying Zong _{2,

3} , Zhonggan Ren ₁ , Juntao Hu ₁ , Xinyuan Wu ₁ , Honglei Xiao ₁ , Song Qin _{1,

4} , Guomin Zhou _{1,

4} , Yuanyuan Ma ₅ , Yaodong Zhang ₆ , Jin Yu ₇ , Kaidi Wang ₈ , Guocai Lu _{2,

3} , Qiong Liu _{1,

4}

Affiliation

In the brain, NLRP3 (Nucleotide‐binding oligomerization domain, leucine‐rich repeat, and pyrin‐domain‐containing 3) inflammasome is mainly expressed in microglia located in the hippocampus and other mood‐regulated regions, which are particularly susceptible to stress. The activation of NLRP3 inflammasome and production of the activation products may contribute to the development of depressive disorder and memory deficits. Indoleamine 2, 3‐dioxygenase (IDO) is a key factor mediating inflammation and major depressive disorder (MDD). We here generated NLRP3 and apoptosis‐associated speck‐like protein containing caspase recruitment domain (ASC)‐knockout mice, respectively, to verify the effects of NLRP3 or ASC deficiency on lipopolysaccharide (LPS)‐induced depressive‐like behaviors, neuroinflammation, and regulation of IDO expression. Furthermore, we treated these mice with the antidepressant clomipramine (CLO) to observe its effect on depressive‐like behaviors and the expression of the NLRP3 inflammasome and LPS‐induced IDO. We found that intraperitoneal LPS administration led to marked depressive‐like behavior and neuroinflammation. NLRP3 or ASC deficiency attenuated LPS‐induced depressive‐like symptoms and increased IDO gene expression, which was accompanied by inhibition of LPS‐induced microglial activation, suggesting that IDO may be a downstream mediator of the NLRP3 inflammasome in inflammation‐mediated depressive‐like behaviors. Clomipramine administration ameliorated depressive‐like behavior in LPS‐treated mice by regulating the expression of ASC and IDO. In conclusion, NLRP3 inflammasome is involved in LPS‐induced depressive‐like behaviors, and that NLRP3 and ASC may play roles in regulating IDO expression in microglia. This may be a potential mechanism for its involvement in MDD. The antidepressant effect of clomipramine may be exerted through the regulation of ASC‐mediated expression of IDO.

中文翻译：

NLRP3炎性小体在脂多糖诱导的抑郁样行为中对海马小胶质细胞中吲哚胺2、3-二加氧酶的调节

在大脑中，NLRP3（结合核苷酸的寡聚域，富含亮氨酸的重复序列和含有含吡啶结构域的3）炎症小体主要在海马和其他情绪调节区域的小胶质细胞中表达，特别容易受到压力的影响。NLRP3炎性小体的活化和活化产物的产生可能有助于抑郁症和记忆障碍的发展。吲哚胺2、3-二加氧酶（IDO）是介导炎症和重度抑郁症（MDD）的关键因素。我们在这里分别生成了NLRP3和凋亡相关的斑点样蛋白，含caspase募集域（ASC）敲除小鼠，以验证NLRP3或ASC缺乏对脂多糖（LPS）诱导的抑郁样行为，神经炎症和调节的影响IDO表达。此外，我们用抗抑郁药氯米帕明（CLO）处理了这些小鼠，以观察其对抑郁样行为的影响以及NLRP3炎性小体和LPS诱导的IDO的表达。我们发现腹膜内给予LPS会导致明显的抑郁样行为和神经炎症。NLRP3或ASC缺乏症减轻LPS诱导的抑郁样症状并增加IDO基因表达，同时抑制LPS诱导的小胶质细胞活化，这表明IDO在炎症介导的抑郁样行为中可能是NLRP3炎症小体的下游介质。。氯米帕明给药可通过调节ASC和IDO的表达改善LPS治疗小鼠的抑郁样行为。总之，NLRP3炎性体与LPS诱导的抑郁样行为有关，NLRP3和ASC可能在小胶质细胞中IDO表达的调节中发挥作用。这可能是其参与MDD的潜在机制。氯米帕明的抗抑郁作用可以通过调节ASC介导的IDO表达来发挥。

更新日期：2020-11-21

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