Chronic glucocorticoids exposure enhances neurodegeneration in the frontal cortex and hippocampus via NLRP-1 inflammasome activation in male mice

Wen, Hao; Zhang, Yaodong; Wu, Wen Li; Yin, Yong; Huang, Dake; Wang, Yuchan; Li, Weiping; Li, Weizu

doi:10.1016/j.bbi.2015.09.019

Cited by 69 publications

(61 citation statements)

References 64 publications

(74 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A growing body of evidence has confirmed that the activation of microglia and overproduction of proinflammatory cytokines in some brain areas are associated with the development of these diseases [75–78]. Many studies of depression [79–82] have demonstrated peripheric inflammation activation, including elevated levels of IL-1β, IL-6 and interferon-γ (IFN-γ) in peripheral circulation in depressive patients or animal model of depression, but only several studies observed the increased concentration of IL-1β in some brain regions in animal model of depression[33, 83, 84]. In recent years, activated microglia was regarded as the source of local synthesized cytokines in brain.…”

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

255

174

View full text Add to dashboard Cite

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.

show abstract

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

255

174

View full text Add to dashboard Cite

show abstract

“…For the PCR analysis, total RNA was extracted from hippocampus tissues and cultured hippocampal neurons with TRIzol reagent (Invitrogen Co., USA) according to the manufacturer’s instructions as described previously [27]. The first-strand cDNA was synthesized from total RNA with PrimeScript™ Reverse Transcriptase (Takara Bio) according to the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

“…It has been reported that chronic GC exposure increased the gene expression of NLRP3, Iba-1, MHCII, and NF-κBIα in a concentration-dependent manner in microglia [21]. Our latest study showed that chronic dexamethasone (DEX) treatment (21 and 28 days) induced significant neurodegeneration and activated NLRP1 inflammasome in the frontal cortex and hippocampus brain tissue [27]. However, the precise mechanisms of chronic GC exposure on the activation of NLRP1 inflammasome in hippocampal neurons remain to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Chronic glucocorticoid exposure activates BK-NLRP1 signal involving in hippocampal neuron damage

Zhang

et al. 2017

J Neuroinflammation

Self Cite

View full text Add to dashboard Cite

BackgroundNeuroinflammation mediated by NLRP1 (nucleotide-binding oligomerization domain (NOD)-like receptor protein 1) inflammasome plays an important role in many neurological diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Our previous studies showed that chronic glucocorticoid (GC) exposure increased brain inflammation via NLRP1 inflammasome and induce neurodegeneration. However, little is known about the mechanism of chronic GC exposure on NLRP1 inflammasome activation in hippocampal neurons.MethodsHippocampal neurons damage was assessed by LDH kit and Hoechst 33258 staining. The expression of microtubule-associated protein 2 (MAP2), inflammasome complex protein (NLRP1, ASC and caspase-1), inflammatory cytokines (IL-1β), and large-conductance Ca2+ and voltage-activated K+ channel (BK channels) protein was detected by Western blot. The inflammatory cytokines (IL-1β and IL-18) were examined by ELISA kit. The mRNA levels of NLRP1, IL-1β, and BK were detected by real-time PCR. BK channel currents were recorded by whole-cell patch-clamp technology. Measurement of [K+]i was performed by ion-selective electrode (ISE) technology.ResultsChronic dexamethasone (DEX) treatment significantly increased LDH release and neuronal apoptosis and decreased expression of MAP2. The mechanistic studies revealed that chronic DEX exposure significantly increased the expression of NLRP1, ASC, caspase-1, IL-1β, L-18, and BK protein and NLRP1, IL-1β and BK mRNA levels in hippocampal neurons. Further studies showed that DEX exposure results in the increase of BK channel currents, with the subsequent K+ efflux and a low concentration of intracellular K+, which involved in activation of NLRP1 inflammasome. Moreover, these effects of chronic DEX exposure could be blocked by specific BK channel inhibitor iberiotoxin (IbTx).ConclusionOur findings suggest that chronic GC exposure may increase neuroinflammation via activation of BK-NLRP1 signal pathway and promote hippocampal neurons damage, which may be involved in the development and progression of AD.

show abstract

“…In adult animals, activation of IKK2 (IKKβ) leads to inflammatory dilated cardiomyopathy and heart failure [36]. NLRs participate in NF-κB signaling [28,37]. According to our results, NLRP1 significantly enhanced the activation of NF-κB by disrupting transcriptional activity.…”

Section: Discussionmentioning

confidence: 72%

Nuclear Localization Leucine-Rich-Repeat Protein 1 Deficiency Protects Against Cardiac Hypertrophy by Pressure Overload

Zong

Liang

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Nuclear localization leucine-rich-repeat protein 1 (NLRP1) is a cytoplasmic protein, involved in autoimmune diseases, mammalian reproduction, neuronal cell death, and stroke. However, the role of NLRP1 in cardiac hypertrophy remains unclear. We used in vivo and in vitro models to investigate the effects of NLRP1 on cardiac hypertrophy. Methods: We used NLRP1-deficient mice and cultured neonatal rat cardiomyocytes with gain and loss of NLRP1 function. Cardiac hypertrophy was estimated by echocardiographic and hemodynamic measurements, and by pathological and molecular analysis. Results: Eight weeks after aortic banding (AB), NLRP1 deficiency significantly inhibited aortic banding–induced cardiac hypertrophy, inflammation, and fibrosis. Activation of MAPK, NF-κB, and TGF-β/Smad pathways was reduced in NLRP1-knockout (KO) mice compared with that in wild-type (WT) mice. Consistent with these results, in vitro studies, performed using cultured neonatal mouse cardiomyocytes, confirmed that NLRP1 deficiency protects against cardiomyocyte hypertrophy induced by isoproterenol (PE); this protective activity was associated with the arrest of MAPK and NF-κB signaling. Conclusions: Our data illustrates that NLRP1 plays a crucial role in the development of cardiac hypertrophy via positive regulation of the MAPK, NF-κB, and TGF-β/Smad signaling pathways.

show abstract

Chronic glucocorticoids exposure enhances neurodegeneration in the frontal cortex and hippocampus via NLRP-1 inflammasome activation in male mice

Cited by 69 publications

References 64 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

Chronic glucocorticoid exposure activates BK-NLRP1 signal involving in hippocampal neuron damage

Nuclear Localization Leucine-Rich-Repeat Protein 1 Deficiency Protects Against Cardiac Hypertrophy by Pressure Overload

Contact Info

Product

Resources

About