Yang Feng, Zhu Wen, Cai Xiaofang, Zhang Wen, Yu Zhonghai, Li Xiangting, Zhang Jingsi, Cai Min, Xiang Jun, Cai Dingfang
Department of Integrative Medicine, Zhongshan Hospital, Fudan University, China; Institute of Neurology, Academy of Integrative Medicine, Fudan University, Shanghai, China.
Department of Traditional Chinese Medicine, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, China.
Biochem Biophys Res Commun. 2020 Jun 4;526(3):553-559. doi: 10.1016/j.bbrc.2020.02.149. Epub 2020 Apr 1.
Inflammasome activation and followed by the release of proinflammatory cytokines play a pivotal role in the development and progression of depression. However, the involvement of gasdermin D (GSDMD)-mediated pyroptosis in inflammasome-associated depression has not been studied. The present study aimed to determine the involvement of pyroptosis in the development of depression.
The rat depressive model was established by the administration of monosodium glutamate (MSG) in postnatal rats. Minocycline (an anti-inflammatory agent) and VX-765 (a specific inhibitor of caspase-1) were given as intervention treatments when rats were two-month-old. Rat depressive behaviors were evaluated by behavioral tests, including open field test, sucrose preference test, and forced swim test. Rat hippocampi were collected for western blotting and immunofluorescence examination.
MSG administration induced depressive-like behavior in rats. MSG upregulated protein presences of caspase-1, GSDMD, interleukin-1β (IL-1β), interleukin-18 (IL-18), NLR pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), high mobility group box 1 protein (HMGB1), and the receptor for advanced glycation end products (RAGE) in the hippocampus. Protein presences of HMGB1, NLRP3 and GSDMD were upregulated in Olig2+ oligodendrocytes in the hippocampus. The data suggest that both HMGB1/RAGE/NLRP3 signalings and GSDMD-dependent pyroptosis were activated. Both minocycline and VX-765 treatments improved depressive-like behaviors. Minocycline treatment significantly reduced both HMGB1/RAGE/NLRP3 inflammasome signalings and GSDMD-dependent pyroptosis. VX-765 downregulated GSDMD-dependent pyroptosis, but not HMGB1/RAGE signalings, indicating that GSDMD-dependent pyroptosis is a key player in the progress of depression.
In rats hippocampus, NLRP3 inflammasome activates GSDMD mediated-pyroptosis in the hippocampus of MSG-induced depressive rats.
炎性小体激活并随后释放促炎细胞因子在抑郁症的发生和发展中起关键作用。然而，gasdermin D（GSDMD）介导的细胞焦亡在炎性小体相关抑郁症中的作用尚未得到研究。本研究旨在确定细胞焦亡在抑郁症发生中的作用。
通过给新生大鼠注射谷氨酸钠（MSG）建立大鼠抑郁模型。当大鼠两个月大时，给予米诺环素（一种抗炎剂）和VX-765（一种半胱天冬酶-1的特异性抑制剂）作为干预治疗。通过行为测试评估大鼠的抑郁行为，包括旷场试验、蔗糖偏好试验和强迫游泳试验。收集大鼠海马进行蛋白质印迹和免疫荧光检查。
给予MSG可诱导大鼠出现抑郁样行为。MSG上调了海马中半胱天冬酶-1、GSDMD、白细胞介素-1β（IL-1β）、白细胞介素-18（IL-18）、含NLR吡咯结构域蛋白3（NLRP3）、凋亡相关斑点样蛋白（ASC）、高迁移率族蛋白B1（HMGB1）以及晚期糖基化终末产物受体（RAGE）的蛋白表达。海马中Olig2+少突胶质细胞中HMGB1、NLRP3和GSDMD的蛋白表达上调。数据表明HMGB1/RAGE/NLRP3信号通路和GSDMD依赖性细胞焦亡均被激活。米诺环素和VX-765治疗均改善了抑郁样行为。米诺环素治疗显著降低了HMGB1/RAGE/NLRP3炎性小体信号通路和GSDMD依赖性细胞焦亡。VX-765下调了GSDMD依赖性细胞焦亡，但未下调HMGB1/RAGE信号通路，表明GSDMD依赖性细胞焦亡是抑郁症进展中的关键因素。
在大鼠海马中，NLRP3炎性小体激活了MSG诱导的抑郁大鼠海马中GSDMD介导的细胞焦亡。
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