Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviorsReportar como inadecuado




Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal of Neuroinflammation

, 14:102

First Online: 10 May 2017Received: 17 February 2017Accepted: 14 April 2017DOI: 10.1186-s12974-017-0865-y

Cite this article as: Yue, N., Huang, H., Zhu, X. et al. J Neuroinflammation 2017 14: 102. doi:10.1186-s12974-017-0865-y

Abstract

BackgroundIn recent years, proinflammatory cytokine interleukin-1β IL-1β was considered to play a critical role in the pathogenesis of depression. In addition, P2X7 receptor P2X7R, a member of the purinergic receptor family, which is predominantly present on microglia, as well as on astrocytes and neurons in lesser amounts in the central nervous system, was suggested to be involved in the processing and releasing of IL-1β. Here, we investigated the role of P2X7R in the pathogenesis of depression.

MethodsMale Sprague-Dawley rats were subjected to chronic unpredictable stressors CUS for 3 weeks. At the end of week 1, 2, and 3, extracellular ATP, caspase 1, IL-1β, and components and activation of NLRP3 inflammasome nucleotide-binding, leucine-rich repeat, pyrin domain containing 3 were evaluated as biomarker of neuroinflammation. In separate experiments, the rats were microinjected with P2X7R agonists ATP, BzATP, and saline into the hippocampus, respectively, or exposed to CUS combined with hippocampal microinjection with P2X7R antagonist, BBG and A438079, and saline, respectively, for 3 weeks, followed by exposed to forced swimming test and open-field test. Moreover, we also evaluated the depressive and anxiety-like behavior of P2X7-null mice in forced swimming test, open-field test, and elevated plus maze.

ResultsAlong with stress accumulation, extracellular ATP, cleaved-caspase 1, IL-1β, and ASC were significantly enhanced in the hippocampus, but P2X7R and NLRP3 were not. Immunoprecipitation assay indicated that along with the accumulation of stress, assembly of NLRP3 inflammasome and cleaved caspase 1 in NLRP3 inflammasome were significantly increased. Moreover, antagonists of P2X7R, either BBG or A438079, prevented the development of depressive-like behaviors induced by chronic unpredictable stress in rats. Meanwhile, we could not observe any depressive-like or anxiety-like behaviors of P2X7-null mice after they had been exposed to CUS. The results implied that P2X7 knockout could impede the development of depressive-like and anxiety-like behaviors induced by CUS. In contrast, chronic administration of agonists of P2X7R, either ATP or BzATP, could induce depressive-like behaviors.

ConclusionsThe activation of P2X7R and subsequent NLRP3 inflammasome in hippocampal microglial cells could mediate depressive-like behaviors, which suggests a new therapeutic target for the prevention and treatment of depression.

KeywordsDepression P2X7 receptor eATP Glia NLRP3 inflammasome AbbreviationsACSFArtificial cerebrospinal fluid

ARL 67156 trisodium salt6-N, N-diethyl-β-γ-dibromomethylene-D-adenosine-5-triphosphate FPL 67156

CUSChronic unpredictable stress

IL-1βInterleukin-1β

IPImmunoprecipitation

P2X7RP2X7 receptor

Electronic supplementary materialThe online version of this article doi:10.1186-s12974-017-0865-y contains supplementary material, which is available to authorized users.





Autor: Na Yue - Huijie Huang - Xiaocang Zhu - Qiuqin Han - Yalin Wang - Bing Li - Qiong Liu - Gencheng Wu - Yuqiu Zhang - Jin Y

Fuente: https://link.springer.com/







Documentos relacionados