Alcohol and Neuroimmunology

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 19744

Special Issue Editor

Neuroscience Department, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Interests: neuroimmune actions on the brain; alcohol/neuroimmune interactions; synaptic transmission; neurophysiology; calcium imaging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Alcohol has been in use as a recreational drug for centuries, with the downside that it has negative impacts on body function, results in problematic behavior, and is addictive. There is considerable interest in the mechanisms underlying these effects of alcohol, particularly with respect to the actions of alcohol on the brain, which plays a central role the problematic behavior caused by excess alcohol use and in the development of alcohol use disorders, a widespread disease with limited treatment strategies. 

Considerable research has been directed at an understanding of the interactions of alcohol with the neuronal system of the brain. However, emerging research indicates that glial cells (e.g., astrocytes and microglia) also play an important role in the actions of alcohol on the brain. Glial cells function as an innate immune system of the brain, referred to as the neuroimmune system, and produce signaling factors (e.g., cytokines) that serve as important regulators of brain function, both under physiological and pathological conditions.  It is now known that alcohol interactions with this neuroimmune system play a key role in many effects of alcohol on the brain. 

Although our understanding of the neuroimmune system and its interactions with alcohol are still rather limited, considerable progress has been made. This Special Issue focuses on this emerging area of research and studies that are providing critical insight into alcohol–neuroimmune interactions, potential therapeutic targets, and potential  treatment strategies. 

Prof. Dr. Donna Gruol
Guest Editor

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Keywords

  • astrocyte
  • microglia
  • cytokine
  • neuroinflammation
  • neurotoxicity
  • brain
  • gene regulation
  • signal transduction
  • mitochondria
  • alcohol use disorders

Published Papers (13 papers)

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Research

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17 pages, 3900 KiB  
Article
Adolescent Intermittent Ethanol Drives Modest Neuroinflammation but Does Not Escalate Drinking in Male Rats
by Jessica I. Wooden, Lauren E. Peacoe, Chinchusha Anasooya Shaji, Jennifer K. Melbourne, Cassie M. Chandler, Michael T. Bardo and Kimberly Nixon
Cells 2023, 12(21), 2572; https://doi.org/10.3390/cells12212572 - 04 Nov 2023
Cited by 1 | Viewed by 1443
Abstract
During adolescence, the brain is highly susceptible to alcohol-induced damage and subsequent neuroimmune responses, effects which may enhance development of an alcohol use disorder (AUD). Neuroimmune reactions are implicated in adolescent alcohol exposure escalating adulthood drinking. Therefore, we investigated whether intermittent alcohol exposure [...] Read more.
During adolescence, the brain is highly susceptible to alcohol-induced damage and subsequent neuroimmune responses, effects which may enhance development of an alcohol use disorder (AUD). Neuroimmune reactions are implicated in adolescent alcohol exposure escalating adulthood drinking. Therefore, we investigated whether intermittent alcohol exposure in male, adolescent rats (AIE) escalated adult drinking via two-bottle choice (2BC). We also examined the influence of housing environment across three groups: standard (group-housed with enrichment during 2BC), impoverished (group-housed without enrichment during 2BC), or isolation (single-housed without bedding or enrichment throughout). In the standard group immediately after AIE/saline and after 2BC, we also examined the expression of microglial marker, Iba1, reactive astrocyte marker, vimentin, and neuronal cell death dye, FluoroJade B (FJB). We did not observe an escalation of adulthood drinking following AIE, regardless of housing condition. Further, only a modest neuroimmune response occurred after AIE in the standard group: no significant microglial reactivity or neuronal cell death was apparent using this model, although some astrocyte reactivity was detected in adolescence following AIE that resolved by adulthood. These data suggest that the lack of neuroimmune response in adolescence in this model may underlie the lack of escalation of alcohol drinking, which could not be modified through isolation stress. Full article
(This article belongs to the Special Issue Alcohol and Neuroimmunology)
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23 pages, 2332 KiB  
Article
Impact of Elevated Brain IL-6 in Transgenic Mice on the Behavioral and Neurochemical Consequences of Chronic Alcohol Exposure
by Donna L. Gruol, Delilah Calderon, Salvador Huitron-Resendiz, Chelsea Cates-Gatto and Amanda J. Roberts
Cells 2023, 12(18), 2306; https://doi.org/10.3390/cells12182306 - 19 Sep 2023
Viewed by 816
Abstract
Alcohol consumption activates the neuroimmune system of the brain, a system in which brain astrocytes and microglia play dominant roles. These glial cells normally produce low levels of neuroimmune factors, which are important signaling factors and regulators of brain function. Alcohol activation of [...] Read more.
Alcohol consumption activates the neuroimmune system of the brain, a system in which brain astrocytes and microglia play dominant roles. These glial cells normally produce low levels of neuroimmune factors, which are important signaling factors and regulators of brain function. Alcohol activation of the neuroimmune system is known to dysregulate the production of neuroimmune factors, such as the cytokine IL-6, thereby changing the neuroimmune status of the brain, which could impact the actions of alcohol. The consequences of neuroimmune–alcohol interactions are not fully known. In the current studies we investigated this issue in transgenic (TG) mice with altered neuroimmune status relative to IL-6. The TG mice express elevated levels of astrocyte-produced IL-6, a condition known to occur with alcohol exposure. Standard behavioral tests of alcohol drinking and negative affect/emotionality were carried out in homozygous and heterozygous TG mice and control mice to assess the impact of neuroimmune status on the actions of chronic intermittent alcohol (ethanol) (CIE) exposure on these behaviors. The expressions of signal transduction and synaptic proteins were also assessed by Western blot to identify the impact of alcohol–neuroimmune interactions on brain neurochemistry. The results from these studies show that neuroimmune status with respect to IL-6 significantly impacts the effects of alcohol on multiple levels. Full article
(This article belongs to the Special Issue Alcohol and Neuroimmunology)
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13 pages, 2271 KiB  
Communication
Ethanol Induces Neuroinflammation in a Chronic Plus Binge Mouse Model of Alcohol Use Disorder via TLR4 and MyD88-Dependent Signaling
by Kalee N. Holloway, James C. Douglas, Tonya M. Rafferty, Cynthia J. M. Kane and Paul D. Drew
Cells 2023, 12(16), 2109; https://doi.org/10.3390/cells12162109 - 21 Aug 2023
Cited by 1 | Viewed by 1374
Abstract
Ethanol induces neuroinflammation, which is believed to contribute to the pathogenesis of alcohol use disorder (AUD). Toll-like receptors (TLRs) are a group of pattern recognition receptors (PRRs) expressed on both immune cells, including microglia and astrocytes, and non-immune cells in the central nervous [...] Read more.
Ethanol induces neuroinflammation, which is believed to contribute to the pathogenesis of alcohol use disorder (AUD). Toll-like receptors (TLRs) are a group of pattern recognition receptors (PRRs) expressed on both immune cells, including microglia and astrocytes, and non-immune cells in the central nervous system (CNS). Studies have shown that alcohol activates TLR4 signaling, resulting in the induction of pro-inflammatory cytokines and chemokines in the CNS. However, the effect of alcohol on signaling pathways downstream of TLR4, such as MyD88 and TRIF (TICAM) signaling, has not been evaluated extensively. In the current study, we treated male wild-type, TLR4-, MyD88-, and TRIF-deficient mice using a chronic plus binge mouse model of AUD. Evaluation of mRNA expression by qRT-PCR revealed that ethanol increased IL-1β, TNF-α, CCL2, COX2, FosB, and JunB in the cerebellum in wild-type and TRIF-deficient mice, while ethanol generally did not increase the expression of these molecules in TLR4- and MyD88-deficient mice. Furthermore, IRF3, IRF7, and IFN-β1, which are associated with the TRIF-dependent signaling cascade, were largely unaffected by alcohol. Collectively, these results suggest that the TLR4 and downstream MyD88-dependent signaling pathways are essential in ethanol-induced neuroinflammation in this mouse model of AUD. Full article
(This article belongs to the Special Issue Alcohol and Neuroimmunology)
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22 pages, 2493 KiB  
Article
Intermittent Exposure to a Single Bottle of Ethanol Modulates Stress Sensitivity: Impact of Age at Exposure Initiation
by Paige Marsland, Sarah Trapp, Andrew Vore, Ashley Lutzke, Elena I. Varlinskaya and Terrence Deak
Cells 2023, 12(15), 1991; https://doi.org/10.3390/cells12151991 - 03 Aug 2023
Viewed by 888
Abstract
Alcohol use during adolescence is a serious public health problem, with binge drinking and high-intensity drinking being particularly harmful to the developing adolescent brain. To investigate the adverse consequences of binge drinking and high-intensity adolescent drinking, adolescent rodents were intermittently exposed to ethanol [...] Read more.
Alcohol use during adolescence is a serious public health problem, with binge drinking and high-intensity drinking being particularly harmful to the developing adolescent brain. To investigate the adverse consequences of binge drinking and high-intensity adolescent drinking, adolescent rodents were intermittently exposed to ethanol through intragastric gavage, intraperitoneal injection, or vapor inhalation. These models revealed the long-lasting behavioral and neural consequences of adolescent intermittent ethanol (AIE) exposure. The present study was designed to characterize a different AIE model, namely, intermittent exposure to a single bottle of 10% ethanol as the only source of fluids on a 2 days on/2 days off (water days) schedule, and to determine whether this AIE exposure model would produce changes in hormonal and neuroimmune responsiveness to challenges of differing modalities. Assessments of ethanol intake as well as blood and brain ethanol concentrations (BECs and BrECs, respectively) in adult male and female rats (Experiment 1) revealed that BECs and BrECs peaked following access to ethanol for a 2 h period when assessed 1 h into the dark cycle. Experiment 2 revealed age differences in ethanol intake, BECs, and BrECs following a 2 h access to ethanol (1 h into the dark cycle), with adolescents ingesting more ethanol and reaching higher BECs as well as BrECs than adults. In Experiment 3, intermittent exposure to a single bottle of 10% ethanol for 10 cycles of 2 days on/2 days off was initiated either in early or late adolescence, followed by an acute systemic immune challenge with lipopolysaccharide (LPS) in adulthood. LPS increased corticosterone and progesterone levels regardless of sex and prior ethanol history, whereas an LPS-induced increase in cytokine gene expression in the hippocampus was evident only in ethanol-exposed males and females, with females who underwent early exposure to ethanol being more affected than their later-exposed counterparts. In Experiment 4, intermittent ethanol exposure in females was initiated either in adolescence or adulthood and lasted for 12 ethanol exposure cycles. Then, behavioral (freezing behavior), hormonal (corticosterone and progesterone levels), and neuroimmune (cytokine gene expression in the PVN, amygdala, and hippocampus) responses to novel environments (mild stressors) and shock (intense stressors) were assessed. More pronounced behavioral and hormonal changes, as well as changes in cytokine gene expression, were evident in the shock condition than following placement in the novel environment, with prior history of ethanol exposure not playing a substantial role. Interleukin (IL)-1β gene expression was enhanced by shock in the PVN, whereas shock-induced increases in IL-6 gene expression were evident in the hippocampus. Together, these findings demonstrate that our intermittent adolescent exposure model enhances responsiveness to immune but not stress challenges, with females being more vulnerable to this AIE effect than males. Full article
(This article belongs to the Special Issue Alcohol and Neuroimmunology)
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19 pages, 5123 KiB  
Article
IL-18 Signaling in the Rat Central Amygdala Is Disrupted in a Comorbid Model of Post-Traumatic Stress and Alcohol Use Disorder
by Vittoria Borgonetti, Bryan Cruz, Valentina Vozella, Sophia Khom, Michael Q. Steinman, Ryan Bullard, Shannon D’Ambrosio, Christopher S. Oleata, Roman Vlkolinsky, Michal Bajo, Eric P. Zorrilla, Dean Kirson and Marisa Roberto
Cells 2023, 12(15), 1943; https://doi.org/10.3390/cells12151943 - 27 Jul 2023
Cited by 3 | Viewed by 1165
Abstract
Alcohol use disorder (AUD) and anxiety disorders are frequently comorbid and share dysregulated neuroimmune-related pathways. Here, we used our established rat model of comorbid post-traumatic stress disorder (PTSD)/AUD to characterize the interleukin 18 (IL-18) system in the central amygdala (CeA). Male and female [...] Read more.
Alcohol use disorder (AUD) and anxiety disorders are frequently comorbid and share dysregulated neuroimmune-related pathways. Here, we used our established rat model of comorbid post-traumatic stress disorder (PTSD)/AUD to characterize the interleukin 18 (IL-18) system in the central amygdala (CeA). Male and female rats underwent novel (NOV) and familiar (FAM) shock stress, or no stress (unstressed controls; CTL) followed by voluntary alcohol drinking and PTSD-related behaviors, then all received renewed alcohol access prior to the experiments. In situ hybridization revealed that the number of CeA positive cells for Il18 mRNA increased, while for Il18bp decreased in both male and female FAM stressed rats versus CTL. No changes were observed in Il18r1 expression across groups. Ex vivo electrophysiology showed that IL-18 reduced GABAA-mediated miniature inhibitory postsynaptic currents (mIPSCs) frequencies in CTL, suggesting reduced CeA GABA release, regardless of sex. Notably, this presynaptic effect of IL-18 was lost in both NOV and FAM males, while it persisted in NOV and FAM females. IL-18 decreased mIPSC amplitude in CTL female rats, suggesting postsynaptic effects. Overall, our results suggest that stress in rats with alcohol access impacts CeA IL-18-system expression and, in sex-related fashion, IL-18′s modulatory function at GABA synapses. Full article
(This article belongs to the Special Issue Alcohol and Neuroimmunology)
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20 pages, 6878 KiB  
Article
Role of Chemokine Cxcl12a in Mediating the Stimulatory Effects of Ethanol on Embryonic Development of Subpopulations of Hypocretin/Orexin Neurons and Their Projections
by Nushrat Yasmin, Adam D. Collier, Abdul R. Abdulai, Olga Karatayev, Boyi Yu, Milisia Fam and Sarah F. Leibowitz
Cells 2023, 12(10), 1399; https://doi.org/10.3390/cells12101399 - 16 May 2023
Viewed by 1055
Abstract
Studies in zebrafish and rats show that embryonic ethanol exposure at low-moderate concentrations stimulates hypothalamic neurons expressing hypocretin/orexin (Hcrt) that promote alcohol consumption, effects possibly involving the chemokine Cxcl12 and its receptor Cxcr4. Our recent studies in zebrafish of Hcrt neurons in the [...] Read more.
Studies in zebrafish and rats show that embryonic ethanol exposure at low-moderate concentrations stimulates hypothalamic neurons expressing hypocretin/orexin (Hcrt) that promote alcohol consumption, effects possibly involving the chemokine Cxcl12 and its receptor Cxcr4. Our recent studies in zebrafish of Hcrt neurons in the anterior hypothalamus (AH) demonstrate that ethanol exposure has anatomically specific effects on Hcrt subpopulations, increasing their number in the anterior AH (aAH) but not posterior AH (pAH), and causes the most anterior aAH neurons to become ectopically expressed further anterior in the preoptic area (POA). Using tools of genetic overexpression and knockdown, our goal here was to determine whether Cxcl12a has an important function in mediating the specific effects of ethanol on these Hcrt subpopulations and their projections. The results demonstrate that the overexpression of Cxcl12a has stimulatory effects similar to ethanol on the number of aAH and ectopic POA Hcrt neurons and the long anterior projections from ectopic POA neurons and posterior projections from pAH neurons. They also demonstrate that knockdown of Cxcl12a blocks these effects of ethanol on the Hcrt subpopulations and projections, providing evidence supporting a direct role of this specific chemokine in mediating ethanol’s stimulatory effects on embryonic development of the Hcrt system. Full article
(This article belongs to the Special Issue Alcohol and Neuroimmunology)
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30 pages, 3253 KiB  
Article
Exercise in Adolescence Enhances Callosal White Matter Refinement in the Female Brain in a Rat Model of Fetal Alcohol Spectrum Disorders
by Katrina A. Milbocker, Ian F. Smith, Eric K. Brengel, Gillian L. LeBlanc, Tania L. Roth and Anna Y. Klintsova
Cells 2023, 12(7), 975; https://doi.org/10.3390/cells12070975 - 23 Mar 2023
Cited by 2 | Viewed by 1709
Abstract
A total of 1 in 20 infants born annually are exposed to alcohol prenatally, which disrupts neurodevelopment and results in several disorders categorized under the umbrella term Fetal Alcohol Spectrum Disorders (FASD). Children and adolescents affected by FASD exhibit delayed maturation of cerebral [...] Read more.
A total of 1 in 20 infants born annually are exposed to alcohol prenatally, which disrupts neurodevelopment and results in several disorders categorized under the umbrella term Fetal Alcohol Spectrum Disorders (FASD). Children and adolescents affected by FASD exhibit delayed maturation of cerebral white matter, which contributes to deficits in executive function, visuospatial processing, sensory integration, and interhemispheric communication. Research using animal models of FASD have uncovered that oligoglia proliferation, differentiation, and survival are vulnerable to alcohol teratogenesis in the male brain due in part to the activation of the neuroimmune system during gestation and infancy. A comprehensive investigation of prenatal alcohol exposure on white matter development in the female brain is limited. This study demonstrated that the number of mature oligodendrocytes and the production of myelin basic protein were reduced first in the female corpus callosum following alcohol exposure in a rat model of FASD. Analysis of myelin-related genes confirmed that myelination occurs earlier in the female corpus callosum compared to their counterparts, irrespective of postnatal treatment. Moreover, dysregulated oligodendrocyte number and myelin basic protein production was observed in the male and female FASD brain in adolescence. Targeted interventions that support white matter development in FASD-affected youth are nonexistent. The capacity for an adolescent exercise intervention to upregulate corpus callosum myelination was evaluated: we discovered that volunteer exercise increases the number of mature oligodendrocytes in alcohol-exposed female rats. This study provides critical evidence that oligoglia differentiation is difficult but not impossible to induce in the female FASD brain in adolescence following a behavioral intervention. Full article
(This article belongs to the Special Issue Alcohol and Neuroimmunology)
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20 pages, 2821 KiB  
Article
Cerebellar Transcriptomic Analysis in a Chronic plus Binge Mouse Model of Alcohol Use Disorder Demonstrates Ethanol-Induced Neuroinflammation and Altered Glial Gene Expression
by Kalee N. Holloway, Marisa R. Pinson, James C. Douglas, Tonya M. Rafferty, Cynthia J. M. Kane, Rajesh C. Miranda and Paul D. Drew
Cells 2023, 12(5), 745; https://doi.org/10.3390/cells12050745 - 25 Feb 2023
Cited by 4 | Viewed by 2171
Abstract
Alcohol use disorder (AUD) is one of the most common preventable mental health disorders and can result in pathology within the CNS, including the cerebellum. Cerebellar alcohol exposure during adulthood has been associated with disruptions in proper cerebellar function. However, the mechanisms regulating [...] Read more.
Alcohol use disorder (AUD) is one of the most common preventable mental health disorders and can result in pathology within the CNS, including the cerebellum. Cerebellar alcohol exposure during adulthood has been associated with disruptions in proper cerebellar function. However, the mechanisms regulating ethanol-induced cerebellar neuropathology are not well understood. High-throughput next generation sequencing was performed to compare control versus ethanol-treated adult C57BL/6J mice in a chronic plus binge model of AUD. Mice were euthanized, cerebella were microdissected, and RNA was isolated and submitted for RNA-sequencing. Down-stream transcriptomic analyses revealed significant changes in gene expression and global biological pathways in control versus ethanol-treated mice that included pathogen-influenced signaling pathways and cellular immune response pathways. Microglial-associated genes showed a decrease in homeostasis-associated transcripts and an increase in transcripts associated with chronic neurodegenerative diseases, while astrocyte-associated genes showed an increase in transcripts associated with acute injury. Oligodendrocyte lineage cell genes showed a decrease in transcripts associated with both immature progenitors as well as myelinating oligodendrocytes. These data provide new insight into the mechanisms by which ethanol induces cerebellar neuropathology and alterations to the immune response in AUD. Full article
(This article belongs to the Special Issue Alcohol and Neuroimmunology)
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20 pages, 3212 KiB  
Article
Choline Supplementation Alters Hippocampal Cytokine Levels in Adolescence and Adulthood in an Animal Model of Fetal Alcohol Spectrum Disorders
by Jessica A. Baker, Tamara S. Bodnar, Kristen R. Breit, Joanne Weinberg and Jennifer D. Thomas
Cells 2023, 12(4), 546; https://doi.org/10.3390/cells12040546 - 08 Feb 2023
Cited by 2 | Viewed by 2270
Abstract
Alcohol (ethanol) exposure during pregnancy can adversely affect development, with long-lasting consequences that include neuroimmune, cognitive, and behavioral dysfunction. Alcohol-induced alterations in cytokine levels in the hippocampus may contribute to abnormal cognitive and behavioral outcomes in individuals with fetal alcohol spectrum disorders (FASD). [...] Read more.
Alcohol (ethanol) exposure during pregnancy can adversely affect development, with long-lasting consequences that include neuroimmune, cognitive, and behavioral dysfunction. Alcohol-induced alterations in cytokine levels in the hippocampus may contribute to abnormal cognitive and behavioral outcomes in individuals with fetal alcohol spectrum disorders (FASD). Nutritional intervention with the essential nutrient choline can improve hippocampal-dependent behavioral impairments and may also influence neuroimmune function. Thus, we examined the effects of choline supplementation on hippocampal cytokine levels in adolescent and adult rats exposed to alcohol early in development. From postnatal day (PD) 4–9 (third trimester-equivalent), Sprague–Dawley rat pups received ethanol (5.25 g/kg/day) or sham intubations and were treated with choline chloride (100 mg/kg/day) or saline from PD 10–30; hippocampi were collected at PD 35 or PD 60. Age-specific ethanol-induced increases in interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and keratinocyte chemoattractant/human growth-regulated oncogene (KC/GRO) were identified in adulthood, but not adolescence, whereas persistent ethanol-induced increases of interleukin-6 (IL-6) levels were present at both ages. Interestingly, choline supplementation reduced age-related changes in interleukin-1 beta (IL-1β) and interleukin-5 (IL-5) as well as mitigating the long-lasting increase in IFN-γ in ethanol-exposed adults. Moreover, choline influenced inflammatory tone by modulating ratios of pro- to -anti-inflammatory cytokines. These results suggest that ethanol-induced changes in hippocampal cytokine levels are more evident during adulthood than adolescence, and that choline can mitigate some effects of ethanol exposure on long-lasting inflammatory tone. Full article
(This article belongs to the Special Issue Alcohol and Neuroimmunology)
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Review

Jump to: Research

18 pages, 1357 KiB  
Review
Alcohol and the Brain–Gut Axis: The Involvement of Microglia and Enteric Glia in the Process of Neuro-Enteric Inflammation
by Mohammed A. S. Khan and Sulie L. Chang
Cells 2023, 12(20), 2475; https://doi.org/10.3390/cells12202475 - 18 Oct 2023
Viewed by 1659
Abstract
Binge or chronic alcohol consumption causes neuroinflammation and leads to alcohol use disorder (AUD). AUD not only affects the central nervous system (CNS) but also leads to pathologies in the peripheral and enteric nervous systems (ENS). Thus, understanding the mechanism of the immune [...] Read more.
Binge or chronic alcohol consumption causes neuroinflammation and leads to alcohol use disorder (AUD). AUD not only affects the central nervous system (CNS) but also leads to pathologies in the peripheral and enteric nervous systems (ENS). Thus, understanding the mechanism of the immune signaling to target the effector molecules in the signaling pathway is necessary to alleviate AUD. Growing evidence shows that excessive alcohol consumption can activate neuroimmune cells, including microglia, and change the status of neurotransmitters, affecting the neuroimmune system. Microglia, like peripheral macrophages, are an integral part of the immune defense and represent the reticuloendothelial system in the CNS. Microglia constantly survey the CNS to scavenge the neuronal debris. These cells also protect parenchymal cells in the brain and spinal cord by repairing nerve circuits to keep the nervous system healthy against infectious and stress-derived agents. In an activated state, they become highly dynamic and mobile and can modulate the levels of neurotransmitters in the CNS. In several ways, microglia, enteric glial cells, and macrophages are similar in terms of causing inflammation. Microglia also express most of the receptors that are constitutively present in macrophages. Several receptors on microglia respond to the inflammatory signals that arise from danger-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs), endotoxins (e.g., lipopolysaccharides), and stress-causing molecules (e.g., alcohol). Therefore, this review article presents the latest findings, describing the roles of microglia and enteric glial cells in the brain and gut, respectively, and their association with neurotransmitters, neurotrophic factors, and receptors under the influence of binge and chronic alcohol use, and AUD. Full article
(This article belongs to the Special Issue Alcohol and Neuroimmunology)
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16 pages, 2284 KiB  
Review
Neuroimmune Interactions in Fetal Alcohol Spectrum Disorders: Potential Therapeutic Targets and Intervention Strategies
by Sayani Mukherjee, Prashant Tarale and Dipak K. Sarkar
Cells 2023, 12(18), 2323; https://doi.org/10.3390/cells12182323 - 21 Sep 2023
Viewed by 1282
Abstract
Fetal alcohol spectrum disorders (FASD) are a set of abnormalities caused by prenatal exposure to ethanol and are characterized by developmental defects in the brain that lead to various overt and non-overt physiological abnormalities. Growing evidence suggests that in utero alcohol exposure induces [...] Read more.
Fetal alcohol spectrum disorders (FASD) are a set of abnormalities caused by prenatal exposure to ethanol and are characterized by developmental defects in the brain that lead to various overt and non-overt physiological abnormalities. Growing evidence suggests that in utero alcohol exposure induces functional and structural abnormalities in gliogenesis and neuron–glia interactions, suggesting a possible role of glial cell pathologies in the development of FASD. However, the molecular mechanisms of neuron–glia interactions that lead to the development of FASD are not clearly understood. In this review, we discuss glial cell pathologies with a particular emphasis on microglia, primary resident immune cells in the brain. Additionally, we examine the involvement of several neuroimmune molecules released by glial cells, their signaling pathways, and epigenetic mechanisms responsible for FASD-related alteration in brain functions. Growing evidence suggests that extracellular vesicles (EVs) play a crucial role in the communication between cells via transporting bioactive cargo from one cell to the other. This review emphasizes the role of EVs in the context of neuron–glia interactions during prenatal alcohol exposure. Finally, some potential applications involving nutritional, pharmacological, cell-based, and exosome-based therapies in the treatment of FASD are discussed. Full article
(This article belongs to the Special Issue Alcohol and Neuroimmunology)
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12 pages, 2156 KiB  
Review
The Role of Toll and Nonnuclear NF-κB Signaling in the Response to Alcohol
by Nigel S. Atkinson
Cells 2023, 12(11), 1508; https://doi.org/10.3390/cells12111508 - 30 May 2023
Viewed by 1032
Abstract
An understanding of neuroimmune signaling has become central to a description of how alcohol causes addiction and how it damages people with an AUD. It is well known that the neuroimmune system influences neural activity via changes in gene expression. This review discusses [...] Read more.
An understanding of neuroimmune signaling has become central to a description of how alcohol causes addiction and how it damages people with an AUD. It is well known that the neuroimmune system influences neural activity via changes in gene expression. This review discusses the roles played by CNS Toll-like receptor (TLR) signaling in the response to alcohol. Also discussed are observations in Drosophila that show how TLR signaling pathways can be co-opted by the nervous system and potentially shape behavior to a far greater extent and in ways different than generally recognized. For example, in Drosophila, TLRs substitute for neurotrophin receptors and an NF-κB at the end of a TLR pathway influences alcohol responsivity by acting non-genomically. Full article
(This article belongs to the Special Issue Alcohol and Neuroimmunology)
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18 pages, 762 KiB  
Review
Acute and Chronic Ethanol Effects during Adolescence on Neuroimmune Responses: Consequences and Potential Pharmacologic Interventions
by Kala N. Nwachukwu, Hassan E. Mohammed, DaQuan R. Mebane, Andrew W. Barber, H. Scott Swartzwelder and S. Alex Marshall
Cells 2023, 12(10), 1423; https://doi.org/10.3390/cells12101423 - 18 May 2023
Cited by 2 | Viewed by 1611
Abstract
Heavy ethanol consumption during adolescence has been linked to neuroimmune response dysregulation and cognitive deficits in the developing adolescent brain. During adolescence, the brain is particularly susceptible to the pharmacological effects of ethanol that are induced by acute and chronic bouts of exposure. [...] Read more.
Heavy ethanol consumption during adolescence has been linked to neuroimmune response dysregulation and cognitive deficits in the developing adolescent brain. During adolescence, the brain is particularly susceptible to the pharmacological effects of ethanol that are induced by acute and chronic bouts of exposure. Numerous preclinical rodent model studies have used different ethanol administration techniques, such as intragastric gavage, self-administration, vapor, intraperitoneal, and free access, and while most models indicated proinflammatory neuroimmune responses in the adolescent brain, there are various factors that appear to influence this observation. This review synthesizes the most recent findings of the effects of adolescent alcohol use on toll-like receptors, cytokines, and chemokines, as well as the activation of astrocytes and microglia with an emphasis on differences associated with the duration of ethanol exposure (acute vs. chronic), the amount of exposure (e.g., dose or blood ethanol concentrations), sex differences, and the timing of the neuroimmune observation (immediate vs. persistent). Finally, this review discusses new therapeutics and interventions that may ameliorate the dysregulation of neuroimmune maladaptations after ethanol exposure. Full article
(This article belongs to the Special Issue Alcohol and Neuroimmunology)
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