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RationaleAlcohol has both acute and chronic effects on neuroimmune signaling, including triggering pro-inflammatory cytokine release by microglia. Minocycline, a second-generation tetracycline antibiotic, inhibits microglial activation and reduces neuroinflammation in preclinical studies. In mice, minocycline also reduces ethanol intake, attenuates ethanol-induced conditioned place preference, and inhibits ethanol-induced microglial activation and pro-inflammatory cytokine release.ObjectiveHere, for the first time, we tested the effects of minocycline on subjective response to ethanol and acute ethanol-induced inflammation in humans.MethodsForty-eight heavy drinkers participated in a double-blind, placebo-controlled trial in which they were randomized to receive placebo, 100 mg, or 200 mg of minocycline for 10 days. Each subject then underwent two experimental sessions in which they were given a fixed dose of intravenous ethanol using a “clamp” procedure (100 mg%) or placebo (normal saline) on days 8 and 10 of treatment. ResultsMinocycline was well tolerated, but there was no effect of either dose of minocycline on subjective response to ethanol or ethanol-induced craving; minocycline effects on cognitive function seem to interact with age. Minocycline treatment did not alter serum cytokine levels at baseline or during ethanol-exposure, although certain baseline cytokine levels predict sedative response to ethanol. ConclusionThese findings indicate that a short-term treatment with minocycline may not alter ethanol-related inflammation or subjective response to ethanol in humans. Further research is needed to identify pharmacological agents with robust effects on ethanol-induced inflammation to determine whether neuroimmune modulation represents a viable treatment strategy for alcohol use disorder.

Alcohol ingestion is a widespread habituation that evolved along with a growing population, altering physiological conditions through immunomodulatory function. There is much research that has reported that consumption of alcohol at low and heavy levels causes different biological impacts, including cellular injury, leading to systemic dysfunction and increased inflammatory markers. In the fate of professional phagocytic cells, efferocytosis is an inevitable mechanism activated by the apoptotic cells, thus eliminating them and preventing the accumulation of cell corpses/debris in the microenvironment. Subsequently, it promotes the tissue repair mechanism and maintains cellular homeostasis. Unfortunately, defective efferocytosis is widely found in several inflammatory and age-related diseases such as atherosclerosis, autoimmune diseases, lung injury, fatty liver disease, and neurodegenerative diseases. Alcohol abuse is one of the factors that provoke an immune response that increases the rate of morbidity and mortality in parallel in systemic disease patients. Information regarding the emergence of immunomodulation during alcoholic pathogenesis and its association with efferocytosis impairment remain elusive. Hence, here in this review, we discussed the mechanism of efferocytosis, the role of defective efferocytosis in inflammatory diseases, and the role of alcohol on efferocytosis impairment.

Neuroinflammation can be an important factor of many disorders in central nervous system (CNS) including cognitive dysfunction, affective disorders, and addictive behavior associated with prenatal alcohol exposure and presented in early adulthood. In this study we used an experimental rodent model of prenatal alcohol (PA) exposure (consumption of a 10% ethanol solution by female Wistar rats throughout pregnancy), multiplex immunofluorescence analysis of interleukins (IL-1α, IL-1β, IL-3, IL-6, IL-9, and IL-12), tumor necrosis factor (TNF-α), and chemokine CCL5, as well as quantitative real-time PCR to assess the level of cytokine mRNAs in the prefrontal cortex of the sexually mature (PND60) offspring – male and female rats with prenatal alcohol intoxication and control animals. Significant decrease in the content of TNF-α and interleukins IL-1β, IL-3, IL-6, IL-9 was detected in the prefrontal cortex of male, but not in the female PA offspring. Importantly, PA males also showed decrease in the level of TNF-α mRNA in the prefrontal cortex by 45% compared to the control males, which may underlie the detected decrease in its content. Taken together, our study demonstrates that a number of neuroimmune factors are regulated in a sex-specific manner in the prefrontal cortex and are differentially affected in males and females by the prenatal exposure to alcohol. Sex factor must be taken into account when conducting further translational studies of the fetal alcohol spectrum disorders and developing new methods for prevention and therapy.

Increasing evidence points at a role for the immune system in the genesis of the alcohol hangover. This study investigated the association between self-reported immune function and experiencing hangovers. Dutch students aged 18 to 30 years old were invited to complete an online survey. Eighteen items on immune-related complaints were completed to assess self-reported immune function. Alcohol consumption in the past month (with respect to usual consumption and the occasion of heaviest drinking) was also recorded. Subjects with an estimated blood alcohol concentration (eBAC) of 0.18% or higher on their heaviest drinking occasion in the prior month were included in the analyses. Self-reported immune function was compared between drinkers with a hangover and those who claimed to be hangover resistant. In total, of 481 subjects (79.2% women) with a mean (SD) age of 21.1 (1.9) years old were included in the analysis. Of these, 83.3% (n = 400) reported having hangovers and 16.8% (n = 81) claimed to be hangover resistant. Drinkers with hangovers had significantly higher self-reported overall immune function scores when compared to hangover-resistant drinkers (mean ± SD = 10.5 ± 3.6 versus 13.1 ± 4.9, p = 0.0001), indicating a poorer immune status. In conclusion, experiencing alcohol hangovers is associated with significantly poorer self-reported immune function.

miRNA155 has been implicated in normal T cell function and their differentiations into the Th1 subtype. We have shown that acute alcohol (ethanol) intoxication combined with burn injury suppresses T cell IFN-γ release. Herein, we examined whether the decrease in IFN-γ is resulted from altered expression of miRNA155 and transcription factors--NFAT, Tbx21, Jun and Fos--in T cells following ethanol and burn injury. Mice received ethanol (∼3 g/Kg) 4 hours prior to ∼12.5% total body surface area sham or burn injury and were sacrificed one day after injury. Splenic T cells were harvested and cultured with anti-CD3 (2 µg/ml) in the presence or absence of rIL-12 (10 ng/ml) or PMA (10 ng/ml) plus ionomycin (50 ng/ml) for 48 hours. We observed a significant decrease in miRNA155, NFAT, Tbx21, Jun and Fos expression as well as IFN-γ release in T cells cultured with anti-CD3 following ethanol and burn injury compared with shams. The co-treatment of T cells with rIL-12 prevented the decrease in IFN-γ and NFAT, Tbx21, Jun and Fos, but not miRNA155. In contrast, the co-treatment with PMA plus ionomycin normalized the expression of NFAT. It did not prevent the decrease in IFN-γ, Tbx21, Jun, Fos and miRNA155. Finally, results obtained in miRNA155-/- mice did not show any change in T cell release of IFN-γ or expression of nuclear factors compared to wildtype mice. Together, these findings suggest that while ethanol and burn injury decreases the expression of miRNA155, it may not be involved in decreased IFN-γ under those conditions.

On November 21, 2014 the 19th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held at Loyola University Chicago Health Sciences Campus in Maywood, Illinois. The meeting focused broadly on inflammatory cell signaling responses in the context of alcohol and alcohol-use disorders, and was divided into four plenary sessions focusing on the gut and liver, lung infections, general systemic effects of alcohol, and neuro-inflammation. One common theme among many talks was the differential roles of macrophages following both chronic and acute alcohol intoxication. Macrophages were shown to play significant roles in regulating inflammation, oxidative stress, and viral infection following alcohol exposure in the liver, lungs, adipose tissue, and brain. Other work examined the role of alcohol on disease progression in a variety of pathologies including psoriasis, advanced stage lung disease, and cancer. •Inflammatory cell signaling responses in the context of alcohol use disorders.•Roles of macrophages following both chronic and acute alcohol intoxication.•Neuroinflammatory responses following alcohol exposure.

Recent studies indicate that toll-like receptors (TLRs) are expressed on T cells and that these receptors directly or indirectly activate the adaptive immune system. We have shown previously that acute alcohol/ethanol (EtOH) intoxication combined with burn injury suppresses mesenteric lymph node (MLN) T-cell interleukin-2 (IL-2) and interferon γ (IFN-γ) production. We examined whether direct stimulation of T cells with TLR2, 4, 5 and 7 agonists modulates CD3-mediated T-cell IL-2/IFN-γ release following EtOH and burn injury. Male mice were gavaged with EtOH (2.9 gm/kg) 4 h prior to receiving an ~12.5% total body surface area sham or full-thickness burn injury. Animals were killed on d 1 after injury and T cells were purified from MLN and spleens. T cells were cultured with plate-bound anti-CD3 in the presence or absence of various TLR ligands. Although TLR2, 4 and 5 agonists potentiate anti-CD3-dependent IFN-γ by T cells, the TLR2 agonist alone induced IFN-γ production independent of CD3 stimulation. Furthermore, T cells were treated with inhibitors of myeloid differentiation primary response protein 88 (MyD88), TIR domain-containing adaptor protein (TIRAP), p38 and/or extracellular signal-regulated kinase (ERK) to determine the mechanism by which TLR2 mediates IL-2/IFN-γ production. IL-2 was not influenced by TLR agonists. MyD88 and TIRAP inhibitory peptides dose-dependently diminished the ability of T cells to release IFN-γ. p38 and ERK inhibitors also abolished TLR2-mediated T-cell IFN-γ. Together, our findings suggest that TLR2 directly modulates T-cell IFN-γ production following EtOH and burn injury, independent of antigen-presenting cells. Furthermore, we demonstrated that MyD88/TIRAP-dependent p38/ERK activation is critical to TLR2-mediated T-cell IFN-γ release following EtOH and burn injury.

Alcohol intoxication is being recognized increasingly as the major factor in pathogenesis after burn injury. Findings from multiple studies support the suggestion that, in comparison with burn-injured patients who sustained injury in the absence of alcohol intoxication, burn-injured patients who sustained injury under the influence of alcohol exhibit higher rates of infection and are more likely to die. Thus, infection becomes the primary cause of death in burn-injured patients. Because the intestine is considered to be a major source of bacteria, studies in experimental animals have been designed to examine whether alcohol intoxication before burn injury enhances bacterial translocation from the intestine. Results of these studies have shown a several-fold increase in bacterial translocation from the intestine in the group of animals receiving combined insult of alcohol intoxication and burn injury compared with findings for the groups receiving either insult alone. Alcohol intoxication and burn injury independent of each other have also been shown to cause an increase in bacterial translocation. The gastrointestinal tract normally maintains a physical mucosal and immunologic barrier that provides an effective defense in keeping bacteria within the intestinal lumen. However, in injury conditions these defense mechanisms are impaired. Intestinal bacteria consequently gain access to extraintestinal sites. Intestine-derived bacteria are implicated in causing systemic infection and in subsequent multiple organ dysfunction in both immunocompromised patients and patients with injury, such as burn and trauma. In this article, we discuss three potential mechanisms that are likely to contribute to the increase in bacterial translocation in alcohol intoxication and burn injury: (1) increase in bacterial growth in the intestine, (2) physical disruption of mucosal barrier of the intestine, and (3) suppression of the immune defense in the intestine.

Alcohol intoxication impairs neutrophil function and increases host susceptibility to Streptococcus pneumoniae. In a rat model of pneumonia, the effects of acute intoxication were monitored for lung chemokine responses, neutrophil recruitment, and bactericidal activity. Alcohol delayed lung neutrophil recruitment, increased bacterial burden, and decreased survival. Before neutrophil recruitment, bronchoalveolar lavage (BAL) macrophage inflammatory protein–2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC) were decreased by alcohol. This alcohol-induced effect was reversed at 6 h, when there were large numbers of neutrophils in control BAL fluid, compared with the alcohol-treated group. Cyclophosphamide-induced neutropenia decreased neutrophil recruitment, minimizing the effects of recruited neutrophils on chemokine levels, and extended the alcohol-induced chemokine suppression. MIP-2 and CINC mRNA contents also were suppressed by alcohol 4 and 6 h after infection. Thus, alcohol suppresses lung chemokine activity in response to S. pneumoniae which is associated with delayed neutrophil delivery, elevated bacterial burden, and increased mortality