Inhibition of the Inflammasome Signaling Cascade Reduces Alcohol Consumption in Female But Not Male Mice

Lowe, Patrick; Cho, Yeonhee; Tornai, Dávid; Çoban, Şahin; Catalano, Donna; Szabó, Gyöngyi

doi:10.1111/acer.14272

Cited by 18 publications

(17 citation statements)

References 56 publications

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“…Previously, we have used various inhibitors of the proinflammatory NLRP3 inflammasome to show that reduction in inflammation via small molecule inhibitors may affect alcohol consumption and preference. Using therapeutic treatments to inhibit NLRP3, caspase-1, and IL-1β, we found a reduction in ethanol consumption and preference in a two-bottle choice test [18]. Thus, in the treatment of alcohol-related pathology such as alcoholic liver disease, some therapeutics may operate via a mechanism that includes reduced alcohol consumption.…”

Section: Discussionmentioning

confidence: 92%

“…A continuous access (24 h access) two-bottle choice between alcohol and drinking water was used to measure alcohol consumption [18]. Briefly, mice were housed singly and were provided two water-only graduated glass feeders [19] for a 1-day acclimation period along with a chow diet which was provided ad libitum throughout the experiment.…”

Section: Two-bottle Choice Testmentioning

confidence: 99%

“…In the event of leakage from a feeder or if cage bedding was stuffed into the feeder by a mouse, data from that cage for that day was excluded from the analysis. Alcohol consumption and preference were calculated as previously described [18]. Some wild-type female C57BL/6J were treated with daily i.p.…”

Section: Two-bottle Choice Testmentioning

confidence: 99%

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Chronic alcohol-induced neuroinflammation involves CCR2/5-dependent peripheral macrophage infiltration and microglia alterations

Lowe

Morel

Ambade

et al. 2020

J Neuroinflammation

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Background Chronic alcohol consumption is associated with neuroinflammation, neuronal damage, and behavioral alterations including addiction. Alcohol-induced neuroinflammation is characterized by increased expression of proinflammatory cytokines (including TNFα, IL-1β, and CCL2) and microglial activation. We hypothesized chronic alcohol consumption results in peripheral immune cell infiltration to the CNS. Since chemotaxis through the CCL2-CCR2 signaling axis is critical for macrophage recruitment peripherally and centrally, we further hypothesized that blockade of CCL2 signaling using the dual CCR2/5 inhibitor cenicriviroc (CVC) would prevent alcohol-induced CNS infiltration of peripheral macrophages and alter the neuroinflammatory state in the brain after chronic alcohol consumption. Methods C57BL/6J female mice were fed an isocaloric or 5% (v/v) ethanol Lieber DeCarli diet for 6 weeks. Some mice received daily injections of CVC. Microglia and infiltrating macrophages were characterized and quantified by flow cytometry and visualized using CX3CR1eGFP/+ CCR2RFP/+ reporter mice. The effect of ethanol and CVC treatment on the expression of inflammatory genes was evaluated in various regions of the brain, using a Nanostring nCounter inflammation panel. Microglia activation was analyzed by immunofluorescence. CVC-treated and untreated mice were presented with the two-bottle choice test. Results Chronic alcohol consumption induced microglia activation and peripheral macrophage infiltration in the CNS, particularly in the hippocampus. Treatment with CVC abrogated ethanol-induced recruitment of peripheral macrophages and partially reversed microglia activation. Furthermore, the expression of proinflammatory markers was upregulated by chronic alcohol consumption in various regions of the brain, including the cortex, hippocampus, and cerebellum. Inhibition of CCR2/5 decreased alcohol-mediated expression of inflammatory markers. Finally, microglia function was impaired by chronic alcohol consumption and restored by CVC treatment. CVC treatment did not change the ethanol consumption or preference of mice in the two-bottle choice test. Conclusions Together, our data establish that chronic alcohol consumption promotes the recruitment of peripheral macrophages into the CNS and microglia alterations through the CCR2/5 axis. Therefore, further exploration of the CCR2/5 axis as a modulator of neuroinflammation may offer a potential therapeutic approach for the treatment of alcohol-associated neuroinflammation.

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Section: Discussionmentioning

confidence: 92%

Section: Two-bottle Choice Testmentioning

confidence: 99%

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Chronic alcohol-induced neuroinflammation involves CCR2/5-dependent peripheral macrophage infiltration and microglia alterations

Lowe

Morel

Ambade

et al. 2020

J Neuroinflammation

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“…In the context of substance abuse, studies in mice administrated 5% ethanol for 5 weeks, demonstrated increased expression of NLRP1, along with the increased expression of NLRP3, ASC, and proinflammatory cytokines, thus underscoring the ability of alcohol to activate the inflammasomes [ 88 ]. Recent studies from the same group have shown that inhibition of the inflammasome signaling cascade using VX765 and MCC950 reduced alcohol consumption in female mice, further validating the involvement of alcohol in activation of the inflammasome pathway and ensuing neuroinflammation [ 89 ]. In another study in an ex vivo model of organotypic hippocampal-entorhinal cortex brain slice cultures, the inflammasome signaling was shown to mediate ethanol mediated inhibition of hippocampal neurogenesis [ 90 ].…”

Section: Inflammasomesmentioning

confidence: 99%

Role of Inflammasomes in HIV-1 and Drug Abuse Mediated Neuroinflammaging

Sil

Niu

Chivero

et al. 2020

Cells

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Despite the effectiveness of combined antiretroviral therapy (cART) in suppressing virus replication, chronic inflammation remains one of the cardinal features intersecting HIV-1, cART, drug abuse, and likely contributes to the accelerated neurocognitive decline and aging in people living with HIV-1 (PLWH) that abuse drugs. It is also estimated that ~30–60% of PLWH on cART develop cognitive deficits associated with HIV-1-associated neurocognitive disorders (HAND), with symptomatology ranging from asymptomatic to mild, neurocognitive impairments. Adding further complexity to HAND is the comorbidity of drug abuse in PLWH involving activated immune responses and the release of neurotoxins, which, in turn, mediate neuroinflammation. Premature or accelerated aging is another feature of drug abusing PLWH on cART regimes. Emerging studies implicate the role of HIV-1/HIV-1 proteins, cART, and abused drugs in altering the inflammasome signaling in the central nervous system (CNS) cells. It is thus likely that exposure of these cells to HIV-1/HIV-1 proteins, cART, and/or abused drugs could have synergistic/additive effects on the activation of inflammasomes, in turn, leading to exacerbated neuroinflammation, ultimately resulting in premature aging referred to as “inflammaging” In this review, we summarize the current knowledge of inflammasome activation, neuroinflammation, and aging in central nervous system (CNS) cells such as microglia, astrocytes, and neurons in the context of HIV-1 and drug abuse.

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“…Since a great body of evidence indicates that compared with their male counterparts, women are more susceptible to the toxic effects of ethanol in the liver for any given dose of alcohol (Chou, 1994;Greenfield, 2002;Grant et al, 2017;Lowe et al, 2019), and also symptoms and signs in ALD demonstrate sexual dimorphisms, possible gender-related differences in the PD-1/PD-L protein expression were also assessed. Sex hormones have been suggested to influence immune response.…”

Section: Introductionmentioning

confidence: 99%

Gender-related disparities in the frequencies of PD-1 and PD-L1 positive peripheral blood T and B lymphocytes in patients with alcohol-related liver disease: a single center pilot study

Kasztelan-Szczerbińska

Adamczyk

Surdacka

et al. 2021

PeerJ

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Background Exposure to excessive alcohol consumption dysregulates immune signaling. The programed cell death 1 (PD-1) receptor and its ligand PD-L1 play a critical role in the protection against immune-mediated tissue damage. The aim of our study was evaluation of the PD-1/PDL-1 expression on peripheral T and B lymphocytes, its correlation with markers of inflammation and the severity of liver dysfunction in the course of alcohol-related liver disease (ALD). Material and Methods Fifty-six inpatients with ALD (38 males, 18 females, aged 49.23 ± 10.66) were prospectively enrolled and assigned to subgroups based on their: (1) gender, (2) severity of liver dysfunction (Child-Pugh, MELD scores, mDF), (3) presence of ALD complications, and followed for 30 days. Twenty-five age- and gender-matched healthy volunteers served as the control group. Flow cytometric analysis of the PD-1/PD-L1 expression on peripheral lymphocyte subsets were performed. Results General frequencies of PD-1/PD-L1 positive T and B subsets did not differ between the ALD and control group. When patients were analyzed based on their gender, significantly higher frequencies of PD1/PD-L1 positive B cells in ALD females compared to controls were observed. ALD females presented with significantly higher frequencies of PD-1+ and PD-L1+ B cells, as well as PD-L1+ all T cell subsets in comparison with ALD males. The same gender pattern of the PD-1/PDL1 expression was found in the subgroups with mDF > 32 and MELD > 20. No correlations of PD-1+ and PD-L1+ lymphocyte percentages with mDF, CTP and MELD scores, nor with complications of ALD were observed. Significant correlations of PD-L1 positive B cell frequencies with conventional markers of inflammation were found. Conclusions Gender-related differences in the frequencies of PD-1/PD-L1 positive T and B cells were observed in patients with ALD. Upregulation of PD-1+/PD-L1+ lymphocytes paralleled both the severity of alcoholic hepatitis and liver dysfunction in ALD females.

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Inhibition of the Inflammasome Signaling Cascade Reduces Alcohol Consumption in Female But Not Male Mice

Cited by 18 publications

References 56 publications

Chronic alcohol-induced neuroinflammation involves CCR2/5-dependent peripheral macrophage infiltration and microglia alterations

Chronic alcohol-induced neuroinflammation involves CCR2/5-dependent peripheral macrophage infiltration and microglia alterations

Role of Inflammasomes in HIV-1 and Drug Abuse Mediated Neuroinflammaging

Gender-related disparities in the frequencies of PD-1 and PD-L1 positive peripheral blood T and B lymphocytes in patients with alcohol-related liver disease: a single center pilot study

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