Chronic ethanol consumption: role of <scp>TLR3/TRIF</scp>‐dependent signaling

McCarthy, Gizelle M.; Warden, Anna S.; Bridges, Courtney; Blednov, Yuri A.; Harris, R. Adron

doi:10.1111/adb.12539

Cited by 60 publications

(58 citation statements)

References 54 publications

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“…It is important to note that the genomic effects of alcohol consumption vary based on ethanol exposure model, duration, and time following exposure (McCarthy et al, 2017; Osterndorff-Kahanek et al, 2013; 2015; Whitman et al, 2013). Thus, the results from this study present a single snapshot of how alcohol impacts the microglial transcriptome.…”

Section: 4 Conclusionmentioning

confidence: 99%

Microglial-specific transcriptome changes following chronic alcohol consumption

et al. 2018

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Microglia are fundamentally important immune cells within the central nervous system (CNS) that respond to environmental challenges to maintain normal physiological processes. Alterations in steady-state cellular function and over-activation of microglia can facilitate the initiation and progression of neuropathological conditions such as Alzheimer’s disease, Multiple Sclerosis, and Major Depressive Disorder. Alcohol consumption disrupts signaling pathways including both innate and adaptive immune responses that are necessary for CNS homeostasis. Coordinate expression of these genes is not ascertained from an admixture of CNS cell-types, underscoring the importance of examining isolated cellular populations to reveal systematic gene expression changes arising from mature microglia. Unbiased RNA-Seq profiling was used to identify gene expression changes in isolated prefrontal cortical microglia in response to recurring bouts of voluntary alcohol drinking behavior. The voluntary ethanol paradigm utilizes long-term consumption ethanol that results in escalated alcohol intake and altered cortical plasticity that is seen in humans. Gene coexpression analysis identified a coordinately regulated group of genes, unique to microglia, that collectively are associated with alcohol consumption. Genes within this group are involved in toll-like receptor signaling and transforming growth factor beta signaling. Network connectivity of this group identified Siglech as a putative hub gene and highlighted the potential importance of proteases in the microglial response to chronic ethanol. In conclusion, we identified a distinctive microglial gene expression signature for neuroimmune responses related to alcohol consumption that provides valuable insight into microglia-specific changes underlying the development of substance abuse, and possibly other CNS disorders.

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Section: 4 Conclusionmentioning

confidence: 99%

Microglial-specific transcriptome changes following chronic alcohol consumption

et al. 2018

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“…The potential clinical relevance of the interaction between the effects of AUD on the immune system and the possible role of this latter in regulating drinking has received further in vivo validation with the observation that TLR3-TIR-domain-containing adapter-inducing interferon-β (TRIF) pathway are activated during chronic ethanol consumption. The IKKε/TBK1 inhibitor Amlexanox down-regulates TRIF-dependent pathway in the brain and reduces ethanol consumption, suggesting that the TRIF-dependent pathway is implicated in regulation of drinking (26). Hence, the NFKB pathway that lies downstream the activation of TLR signaling may also play a non canonical non-immune role in mediating complex behaviors, including processes of learning and memory, stress responses, anhedonia and drug reward (27).…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic analysis reveals moderate modulation of macrophage migration inhibitory factor superfamily genes in alcohol use disorders

et al. 2020

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Alcohol use disorder (AUD) is a primary, chronic and relapsing disease of brain reward, motivation and memory, which is associated with several comorbidities, including major depression and post-traumatic stress disorder. It has been revealed that Ibudilast (IBUD), a dual inhibitor of phosphodiesterase-4 and-10 and of macrophage migration inhibitory factor (MIF), exerts beneficial effects on AUD in rodent models and human patients. Therefore, IBUD has attracted increasing interest, with research focusing on the elucidation of the pathogenic role of MIF and its homologue, D-dopachrome tautomerase (DDT), in the pathogenesis and maintenance of AUD. By using DNA microarray analysis, the current study performed a transcriptomic expression analysis of MIF, DDT and their co-receptors, including CD74, C-X-C chemokine receptor (CXCR)2, CXCR4 and CXCR7 in patients with AUD. The results revealed that the transcriptomic levels of MIF, DDT and their receptors were superimposable in the prefrontal cortex of rodents and patients with AUD and human patients. Furthermore, peripheral blood cells from heavy drinkers exhibited a moderate increase in MIF and DDT levels, both at the baseline and following exposure to alcohol-associated cues, based on individual situations that included alcohol-related stimuli resulting in subsequent alcohol use (buying alcohol and being at a bar, watching others drink alcohol). Considering the overlapping effects of MIF and DDT, the inverse Fisher's χ 2 test was performed on unadjusted P-values to evaluate the combined effect of MIF and DDT. The results revealed a significant increase in these cytokines in heavy drinkers compared with controls (moderate drinkers). To the best of our knowledge, the present study demonstrated for the first time that MIF and DDT expression was upregulated in the blood of patients with AUD. These results therefore warrant further study to evaluate the role of MIF and DDT in the development and maintenance of AUD, to evaluate their use as biomarkers to predict the psychotherapeutic and pharmacological response of patients with AUD and for use as therapeutic targets.

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“…Acute and chronic ethanol exposure induce an innate immune response in the central nervous system (CNS) of humans, and this effect is replicated in preclinical models of alcohol use disorder (AUD) [1][2][3][4]. Most notably, genomic studies in mice [5], rats [6], and humans [3,7,8] have identified several members of the Toll-like receptors (TLR) and interleukin-1/interleukin18 (IL-1/IL-18) receptor pathways in AUD [9,10].…”

Section: Introductionmentioning

confidence: 99%

“…Most notably, genomic studies in mice [5], rats [6], and humans [3,7,8] have identified several members of the Toll-like receptors (TLR) and interleukin-1/interleukin18 (IL-1/IL-18) receptor pathways in AUD [9,10]. Moreover, pharmacological [11][12][13], viral [14,15], or transgenic [2,9,11,[16][17][18][19][20] manipulation of the innate immune system leads to alterations of the ethanol-related behaviors in rodents. Collectively, this growing literature on innate immune responses critically contributing to the neurobiology of AUD [21][22][23] suggests that these pathways have high potential as targets for the development of new AUD therapeutic strategies [16,[24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Role of MyD88 in IL-1β and Ethanol Modulation of GABAergic Transmission in the Central Amygdala

et al. 2019

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Myeloid differentiation primary response protein (MyD88) is a critical neuroimmune adaptor protein in TLR (Toll-like receptor) and IL-1R (Interleukin-1 receptor) signaling complexes. These two pro-inflammatory families play an important role in the neurobiology of alcohol use disorder, specifically MyD88 regulates ethanol drinking, ethanol-induced sedation, and ethanol-induced deficits in motor coordination. In this study, we examined the role of MyD88 in mediating the effects of IL-1β and ethanol on GABAergic transmission in the central amygdala (CeA) of male mice using whole-cell patch-clamp recordings in combination with pharmacological (AS-1, a mimetic that prevents MyD88 recruitment by IL-1R) and genetic (Myd88 knockout mice) approaches. We demonstrate through both approaches that IL-1β and ethanol’s modulatory effects at CeA GABA synapses are not dependent on MyD88. Myd88 knockout potentiated IL-1β’s actions in reducing postsynaptic GABAA receptor function. Pharmacological inhibition of MyD88 modulates IL-1β’s action at CeA GABA synapses similar to Myd88 knockout mice. Additionally, ethanol-induced CeA GABA release was greater in Myd88 knockout mice compared to wildtype controls. Thus, MyD88 is not essential to IL-1β or ethanol regulation of CeA GABA synapses but plays a role in modulating the magnitude of their effects, which may be a potential mechanism by which it regulates ethanol-related behaviors.

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Chronic ethanol consumption: role of TLR3/TRIF‐dependent signaling

Cited by 60 publications

References 54 publications

Microglial-specific transcriptome changes following chronic alcohol consumption

Microglial-specific transcriptome changes following chronic alcohol consumption

Transcriptomic analysis reveals moderate modulation of macrophage migration inhibitory factor superfamily genes in alcohol use disorders

Role of MyD88 in IL-1β and Ethanol Modulation of GABAergic Transmission in the Central Amygdala

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