Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Doping Control Center, Korea Institute of Science and Technology, Seoul, Republic of Korea; Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
Int J Neuropsychopharmacol. 2017 Nov 1;20(11):896-906. doi: 10.1093/ijnp/pyx065.
Inflammation may play a significant role in the pathogenesis of depression, although the molecular target for the treatment of inflammation-mediated depressive symptoms remains to be elucidated. Recent studies have implicated the NLRP3 inflammasome in various psychiatric disorders, including depression. However, the underlying mechanism by which NLRP3 inflammasome activation mediates the progression of depressive-like behaviors remains poorly understood.
We examined whether NLRP3 deficiency influenced depressive-like behaviors and cerebral inflammation following systemic administration of lipopolysaccharide in mice. To further assess the contribution of the NLRP3 inflammasome to the progression of depression, we evaluated the effects of NLRP3 signaling on levels of indoleamine 2,3-dioxygenase.
Nlrp3-deficient mice exhibited significant attenuation of depressive-like behaviors and cerebral caspase-1 activation in a lipopolysaccharide-induced model of depression. Treatment with the antidepressant amitriptyline failed to block NLRP3-dependent activation of caspase-1, but inhibited lipopolysaccharide-promoted production of interleukin-1β mRNA via suppressing NF-κB signaling in mouse mixed glial cultures. Interestingly, lipopolysaccharide administration produced NLRP3-dependent increases in indoleamine 2,3-dioxygenase expression and activity of mouse brain. Furthermore, inflammasome-activating stimulations, but not treatment with the inflammasome product interleukin-1β, triggered indoleamine 2,3-dioxygenase mRNA induction in mixed glial cells.
Our data indicate that the NLRP3 inflammasome is significantly implicated in the progression of systemic inflammation-induced depression. NLRP3-dependent caspase-1 activation produced significant increases in indoleamine 2,3-dioxygenase levels, which may play a significant role in lipopolysaccharide-induced depression. Collectively, our findings suggest that indoleamine 2,3-dioxygenase is a potential downstream mediator of the NLRP3 inflammasome in inflammation-mediated depressive-like behaviors.
炎症可能在抑郁症的发病机制中起重要作用，尽管治疗炎症介导的抑郁症状的分子靶点仍有待阐明。最近的研究表明，NLRP3 炎性体与各种精神疾病有关，包括抑郁症。然而，NLRP3 炎性体激活介导抑郁样行为进展的潜在机制仍知之甚少。
我们研究了 NLRP3 缺乏是否会影响脂多糖系统给药后小鼠的抑郁样行为和大脑炎症。为了进一步评估 NLRP3 炎性体在抑郁症进展中的作用，我们评估了 NLRP3 信号对吲哚胺 2,3-双加氧酶水平的影响。
NLRP3 缺陷小鼠在脂多糖诱导的抑郁症模型中表现出明显的抑郁样行为和大脑半胱氨酸天冬氨酸蛋白酶-1 激活的减轻。抗抑郁药阿米替林的治疗未能阻断 NLRP3 依赖性半胱氨酸天冬氨酸蛋白酶-1 的激活，但通过抑制 NF-κB 信号通路在小鼠混合神经胶质细胞培养物中抑制脂多糖促进的白细胞介素-1β mRNA 的产生。有趣的是，脂多糖给药导致 NLRP3 依赖性增加吲哚胺 2,3-双加氧酶的表达和小鼠大脑的活性。此外，炎性体激活刺激，但不是炎性体产物白细胞介素-1β 的治疗，触发混合神经胶质细胞中吲哚胺 2,3-双加氧酶 mRNA 的诱导。
我们的数据表明，NLRP3 炎性体在全身炎症诱导的抑郁症进展中具有重要意义。NLRP3 依赖性半胱氨酸天冬氨酸蛋白酶-1 激活导致吲哚胺 2,3-双加氧酶水平显著增加，这可能在脂多糖诱导的抑郁症中起重要作用。总的来说，我们的研究结果表明，吲哚胺 2,3-双加氧酶是炎症介导的抑郁样行为中 NLRP3 炎性体的潜在下游介质。
