NLRP3 inflammasome activation mediates estrogen deficiency-induced depression- and anxiety-like behavior and hippocampal inflammation in mice

Xu, Yue; Sheng, Hui; Bao, Qing-yue; Wang, Yujun; Lu, Jianqiang; Ni, Xin

doi:10.1016/j.bbi.2016.02.022

Cited by 234 publications

(146 citation statements)

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“…In addition, extracellular ATP-induced P2X7R activation could directly mediate K+ efflux which has been proposed to account for NLRP3 activation [93, 94]. Recently, several studies has also reported the change of NLRP3 inflammasome in rodents upon CUMS, LPS stimulus, or estrogen deficiency [95–97]. In their studies, they observed the overexpression of some components of NLRP3 inflammasome but did not detect the assembly of NLRP3 inflammasome.…”

Section: Discussionmentioning

confidence: 99%

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

Yue

Huang

Zhu

et al. 2017

J Neuroinflammation

258

174

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

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Section: Discussionmentioning

confidence: 99%

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

Yue

Huang

Zhu

et al. 2017

J Neuroinflammation

258

174

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“…After mild chronic stress, ovariectomised mice develop depression‐like symptoms that are paralleled by NLRP3 inflammasome activation in the hippocampus . In line with these findings, treatment with the inflammasome inhibitor VX‐765 ameliorated depression‐like behaviour and E 2 administration reversed these effects by acting via nuclear oestrogen receptor‐β (ERβ) . Also of potential interest is the relationship between MD, the action of E 2 and BDNF expression in the brain.…”

Section: Inflammation‐inflammasomes In Major Depressive Disordersmentioning

confidence: 74%

Brain inflammasomes in stroke and depressive disorders: Regulation by oestrogen

Slowik

Lammerding

Hoffmann

et al. 2018

J Neuroendocrinology

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Neuroinflammation is a devastating pathophysiological process that results in brain damage and neuronal death. Pathogens, cell fragments and cellular dysfunction trigger inflammatory responses. Irrespective of the cause, inflammasomes are key intracellular multiprotein signalling platforms that sense neuropathological conditions. The activation of inflammasomes leads to the auto-proteolytic cleavage of caspase-1, resulting in the proteolysis of the pro-inflammatory cytokines interleukin (IL)1β and IL18 into their bioactive forms. It also initiates pyroptosis, a type of cell death. The two cytokines contribute to the pathogenesis in acute and chronic brain diseases and also play a central role in human aging and psychiatric disorders. Sex steroids, in particular oestrogens, are well-described neuroprotective agents in the central nervous system. Oestrogens improve the functional outcome after ischaemia and traumatic brain injury, reduce neuronal death in Parkinson's and Alzheimer's disease, as well as in amyotrophic lateral sclerosis, attenuate glutamate excitotoxicity and the formation of radical oxygen species, and lessen the spread of oedema after damage. Moreover, oestrogens alleviate menopause-related depressive symptoms and have a positive influence on depressive disorders probably by influencing growth factor production and serotonergic brain circuits. Recent evidence also suggests that inflammasome signalling affects anxiety- and depressive-like behaviour and that oestrogen ameliorates depression-like behaviour through the suppression of inflammasomes. In the present review, we highlight the most recent findings demonstrating that oestrogens selectively suppress the activation of the neuroinflammatory cascade in the brain in acute and chronic brain disease models. Furthermore, we aim to describe putative regulatory signalling pathways involved in the control of inflammasomes. Finally, we consider that psychiatric disorders such as depression also contain an inflammatory component that could be modulated by oestrogen.

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“…Astrocytes exhibit decreased secretion of the cytokines and chemokines IL-6, IL-1β, TNFα, IFN-γ-inducible protein 10, and MPP9 following treatment with E2 (Cerciat et al, 2010; Lewis et al, 2008). Consistent with an anti-inflammatory role, ovariectomy-induced E2 depletion results in increased IL-1β levels in the hippocampus via NLRP3 inflammasome, which interacts with the TLR4/NFκB pathway to sustain and further increase inflammation (Xu et al, 2016). On the other hand, E2 administration to astrocytes decreases inflammasome activation as well as NFκB activation, likely by impairing its ability to translocate to the nucleus (Cerciat et al, 2010; Xu et al, 2016).…”

Section: Sex Steroid Hormones and Inflammationmentioning

confidence: 99%

“…Consistent with an anti-inflammatory role, ovariectomy-induced E2 depletion results in increased IL-1β levels in the hippocampus via NLRP3 inflammasome, which interacts with the TLR4/NFκB pathway to sustain and further increase inflammation (Xu et al, 2016). On the other hand, E2 administration to astrocytes decreases inflammasome activation as well as NFκB activation, likely by impairing its ability to translocate to the nucleus (Cerciat et al, 2010; Xu et al, 2016). Furthermore, E2 decreases cell body enlargement of astrocytes, often called astrocytosis, that is associated with age-related increases in inflammation (Lei et al, 2003).…”

Section: Sex Steroid Hormones and Inflammationmentioning

confidence: 99%

Interactions between inflammation, sex steroids, and Alzheimer’s disease risk factors

Uchoa

Moser

Pike

2016

Frontiers in Neuroendocrinology

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Alzheimer’s disease (AD) is an age-related neurodegenerative disorder for which there are no effective strategies to prevent or slow its progression. Because AD is multifactorial, recent research has focused on understanding interactions among the numerous risk factors and mechanisms underlying the disease. One mechanism through which several risk factors may be acting is inflammation. AD is characterized by chronic inflammation that is observed before clinical onset of dementia. Several genetic and environmental risk factors for AD increase inflammation, including apolipoprotein E4, obesity, and air pollution. Additionally, sex steroid hormones appear to contribute to AD risk, with age-related losses of estrogens in women and androgens in men associated with increased risk. Importantly, sex steroid hormones have anti-inflammatory actions and can interact with several other AD risk factors. This review examines the individual and interactive roles of inflammation and sex steroid hormones in AD, as well as their relationships with the AD risk factors apolipoprotein E4, obesity, and air pollution.

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NLRP3 inflammasome activation mediates estrogen deficiency-induced depression- and anxiety-like behavior and hippocampal inflammation in mice

Cited by 234 publications

References 68 publications

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

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

Brain inflammasomes in stroke and depressive disorders: Regulation by oestrogen

Interactions between inflammation, sex steroids, and Alzheimer’s disease risk factors

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