Ethanol directly induced HMGB1 release through NOX2/NLRP1 inflammasome in neuronal cells

Wang, Xiaolan; Chu, Guangpin; Yang, Zhihua; Sun, Yan; Zhou, Hanjing; Li, Man; Shi, Jing; Tian, Bo; Zhang, Chun; Meng, Xianhong

doi:10.1016/j.tox.2015.06.006

Cited by 37 publications

(23 citation statements)

References 41 publications

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“…Similar to our data, HMGB1 is also released from EtOH-treated (50 mM, 24hr) non-differentiated neuroblastoma SH-SY5Y (Wang et al, 2015). Since HMGB1 activates multiple TLRs (Park et al, 2004, Yang et al, 2013), RAGE (Kokkola et al, 2005), and can enhance signaling of cytokines such as IL-1β (Sha et al, 2008), the EtOH-induced HMGB1 release we observe may play a role in proinflammatory signaling in both microglia and neurons.…”

Section: Discussionsupporting

confidence: 91%

Ethanol, TLR3, and TLR4 Agonists Have Unique Innate Immune Responses in Neuron‐Like SH‐SY5Y and Microglia‐Like BV2

Lawrimore

Crews

2017

Alcoholism Clin & Exp Res

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BackgroundEthanol (EtOH) consumption leads to an increase of proinflammatory signaling via activation of Toll‐like receptors (TLRs) such as TLR3 and TLR4 that leads to kinase activation (ERK1/2, p38, TBK1), transcription factor activation (NF κB, IRF3), and increased transcription of proinflammatory cytokines such as TNF‐α, IL‐1β, and IL‐6. This immune signaling cascade is thought to play a role in neurodegeneration and alcohol use disorders. While microglia are considered to be the primary macrophage in brain, it is unclear what if any role neurons play in EtOH‐induced proinflammatory signaling.MethodsMicroglia‐like BV2 and retinoic acid‐differentiated neuron‐like SH‐SY5Y were treated with TLR3 agonist Poly(I:C), TLR4 agonist lipopolysaccharide (LPS), or EtOH for 10 or 30 minutes to examine proinflammatory immune signaling kinase and transcription factor activation using Western blot, and for 24 hours to examine induction of proinflammatory gene mRNA using RT‐PCR.ResultsIn BV2, both LPS and Poly(I:C) increased p‐ERK1/2, p‐p38, and p‐NF κB by 30 minutes, whereas EtOH decreased p‐ERK1/2 and increased p‐IRF3. LPS, Poly(I:C), and EtOH all increased TNF‐α and IL‐1β mRNA, and EtOH further increased TLR2, 7, 8, and MD‐2 mRNA in BV2. In SH‐SY5Y, LPS had no effect on kinase or proinflammatory gene expression. However, Poly(I:C) increased p‐p38 and p‐IRF3, and increased expression of TNF‐α, IL‐1β, and IL‐6, while EtOH increased p‐p38, p‐IRF3, p‐TBK1, and p‐NF κB while decreasing p‐ERK1/2 and increasing expression of TLR3, 7, 8, and RAGE mRNA. HMGB1, a TLR agonist, was induced by LPS in BV2 and by EtOH in both cell types. EtOH was more potent at inducing proinflammatory gene mRNA in SH‐SY5Y compared with BV2.ConclusionsThese results support a novel and unique mechanism of EtOH, TLR3, and TLR4 signaling in neuron‐like SH‐SY5Y and microglia‐like BV2 that likely contributes to the complexity of brain neuroimmune signaling.

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Section: Discussionsupporting

confidence: 91%

Ethanol, TLR3, and TLR4 Agonists Have Unique Innate Immune Responses in Neuron‐Like SH‐SY5Y and Microglia‐Like BV2

Lawrimore

Crews

2017

Alcoholism Clin & Exp Res

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“…While resident immune cells, such as microglia, are principally thought to produce and elaborate inflammatory cytokines, several studies show that human neurons contain an inflammasome [61, 62]. In cultured primary cortical neurons, ethanol can induce caspase-1 activation and HMGB1 release [63]. Primary cortical neuron cultures demonstrate inflammasome activation mediated by K+ efflux in response to acidosis [64].…”

Section: Discussionmentioning

confidence: 99%

Acute fasting inhibits central caspase-1 activity reducing anxiety-like behavior and increasing novel object and object location recognition

et al. 2017

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Background Inflammation within the central nervous system (CNS) is frequently comorbid with anxiety. Importantly, the pro-inflammatory cytokine most commonly associated with anxiety is IL-1β. The bioavailability and activity of IL-1β is regulated by caspase-1-dependent proteolysis vis-a-vis the inflammasome. Thus, interventions regulating the activation or activity of caspase-1 should reduce anxiety especially in states that foster IL-1β maturation. Methods Male C57BL/6j, C57BL/6j mice treated with the capase-1 inhibitor biotin-YVAD-cmk, caspase-1 knockout (KO) mice and IL-1R1 KO mice were fasted for 24 hours or allowed ad libitum access to food. Immediately after fasting, caspase-1 activity was measured in brain region homogenates while activated caspase-1 was localized in the brain by immunohistochemistry. Mouse anxiety-like behavior and cognition were tested using the elevated zero maze and novel object/object location tasks, respectively. Results A 24 h fast in mice reduced the activity of caspase-1 in whole brain and in the prefrontal cortex, amygdala, hippocampus, and hypothalamus by 35%, 25%, 40%, 40%, and 40% respectively. A 24 h fast also reduced anxiety-like behavior by 40% and increased novel object and object location recognition by 21% and 31%, respectively. IL-1β protein, however, was not reduced in the brain by fasting. ICV administration of YVAD decreased caspase-1 activity in the prefrontal cortex and amygdala by 55%, respectively leading to a 64% reduction in anxiety like behavior. Importantly, when caspase-1 KO or IL1-R1 KO mice are fasted, no fasting-dependent reduction in anxiety-like behavior was observed. Conclusions Results indicate that fasting decrease anxiety-like behavior and improves memory by a mechanism tied to reducing caspase-1 activity throughout the brain.

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“…This suggests that inflammasome activation in astrocytes may also contribute to neuroinflammation after brain injury. In contrast, NLRP1 and Aim2 expression has been primarily reported in neurons in the ischemic or injured brain [64–66]. …”

Section: Discussionmentioning

confidence: 99%

NLRP3 Inflammasome Activation in the Brain after Global Cerebral Ischemia and Regulation by 17β‐Estradiol

Thakkar

Wang

Sareddy

et al. 2016

Oxidative Medicine and Cellular Longevity

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17β-Estradiol (E2) is a well-known neuroprotective factor in the brain. Recently, our lab demonstrated that the neuroprotective and cognitive effects of E2 require mediation by the estrogen receptor (ER) coregulator protein and proline-, glutamic acid-, and leucine-rich protein 1 (PELP1). In the current study, we examined whether E2, acting via PELP1, can exert anti-inflammatory effects in the ovariectomized rat and mouse hippocampus to regulate NLRP3 inflammasome activation after global cerebral ischemia (GCI). Activation of the NLRP3 inflammasome pathway and expression of its downstream products, cleaved caspase-1 and IL-1β, were robustly increased in the hippocampus after GCI, with peak levels observed at 6-7 days. Expression of P2X7 receptor, an upstream regulator of NLRP3, was also increased after GCI. E2 markedly inhibited NLRP3 inflammasome pathway activation, caspase-1, and proinflammatory cytokine production, as well as P2X7 receptor expression after GCI (at both the mRNA and protein level). Intriguingly, the ability of E2 to exert these anti-inflammatory effects was lost in PELP1 forebrain-specific knockout mice, indicating a key role for PELP1 in E2 anti-inflammatory signaling. Collectively, our study demonstrates that NLRP3 inflammasome activation and proinflammatory cytokine production are markedly increased in the hippocampus after GCI, and that E2 signaling via PELP1 can profoundly inhibit these proinflammatory effects.

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Ethanol directly induced HMGB1 release through NOX2/NLRP1 inflammasome in neuronal cells

Cited by 37 publications

References 41 publications

Ethanol, TLR3, and TLR4 Agonists Have Unique Innate Immune Responses in Neuron‐Like SH‐SY5Y and Microglia‐Like BV2

Ethanol, TLR3, and TLR4 Agonists Have Unique Innate Immune Responses in Neuron‐Like SH‐SY5Y and Microglia‐Like BV2

Acute fasting inhibits central caspase-1 activity reducing anxiety-like behavior and increasing novel object and object location recognition

NLRP3 Inflammasome Activation in the Brain after Global Cerebral Ischemia and Regulation by 17β‐Estradiol

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