Cerebrospinal Fluid Monocyte Chemoattractant Protein‐1 in Alcoholics: Support for a Neuroinflammatory Model of Chronic Alcoholism

Umhau, John C.; Schwandt, Melanie L.; Solomon, Matthew G.; Yuan, Peixiong; Nugent, Allison C.; Zarate, Carlos A.; Drevets, Wayne C.; Hall, Samuel D.; George, David T.; Heilig, Markus

doi:10.1111/acer.12367

Cited by 38 publications

(26 citation statements)

References 48 publications

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“…In the present studies, we also probed gene expression levels for HMGB1, HSP72, and Mcp-1 (Table 1) because these signaling pathways have been shown to be important for long-term consequences of alcohol exposure and/or are upstream of cytokine gene regulation (Umhau et al, 2014; Whitman et al, 2013). Although on the surface these findings might be viewed as contradictory to prior published work, HMGB1 is not the only mechanism by which NF-κB signaling can be initiated.…”

Section: Discussionmentioning

confidence: 99%

Sustained alterations in neuroimmune gene expression after daily, but not intermittent, alcohol exposure

2016

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Acute ethanol intoxication is associated with Rapid Alterations in Neuroimmune Gene expression (RANGE), including increased Interleukin (IL)-6 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), and suppressed IL-1β and Tumor necrosis factor (TNF) α, yet little is known about adaptations in cytokines across the first few ethanol exposures. Thus, the present studies examined central cytokines during intoxication (3 h post-ethanol) following 2, 4 or 6 intragastric ethanol challenges (4 g/kg) delivered either daily or every-other-day (EOD). Subsequent analyses of blood ethanol concentrations (BECs) and corticosterone were performed to determine whether the schedule of ethanol delivery would alter the pharmacokinetics of, or general sensitivity to, subacute ethanol exposure. As expected, ethanol led to robust increases in IL-6 and IκBα gene expression in hippocampus, amygdala and bed nucleus of the stria terminalis (BNST), whereas IL-1β and TNFα were suppressed, thereby replicating our prior work. Ethanol-dependent increases in IL-6 and IκBα remained significant in all structures—even after 6 days of ethanol. When these doses were administered EOD, modest IL-6 increases in BNST were observed, with TNFα and IL-1β suppressed exclusively in the hippocampus. Analysis of BECs revealed a small but significant reduction in ethanol after 4 EOD exposures — an effect which was not observed when ethanol was delivered after 6 daily intubations. These findings suggest that ethanol-induced RANGE effects are not simply a function of ethanol load per se, and underscore the critical role that ethanol dosing interval plays in determining the neuroimmune consequences of alcohol.

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Section: Discussionmentioning

confidence: 99%

Sustained alterations in neuroimmune gene expression after daily, but not intermittent, alcohol exposure

2016

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“…Additional studies in alcoholics have reported activated microglia and increased concentrations of CCL2 and other inflammatory molecules in multiple brain regions (3, 16). These elevated CCL2 concentrations have also been detected in the cerebrospinal fluid of alcoholics, correlating with plasma concentrations of liver transaminases (17). Chemokines and their receptors are known for their role in liver injury, especially the CC chemokine family in animal models (18), and both alcoholic hepatitis and cirrhosis are associated with distinct patterns of chemokine expression such as CCL8, CCL2, chemokine C-C motif ligand 3 [CCL3, also referred to macrophage inflammatory protein-1 alpha (MIP-1α)], and chemokine C-C motif ligand 4 (CCL4, macrophage inflammatory protein-1 beta) (19).…”

Section: Introductionmentioning

confidence: 91%

Plasma Chemokines in Patients with Alcohol Use Disorders: Association of CCL11 (Eotaxin-1) with Psychiatric Comorbidity

et al. 2017

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Recent studies have linked changes in peripheral chemokine concentrations to the presence of both addictive behaviors and psychiatric disorders. The present study further explore this link by analyzing the potential association of psychiatry comorbidity with alterations in the concentrations of circulating plasma chemokine in patients of both sexes diagnosed with alcohol use disorders (AUD). To this end, 85 abstinent subjects with AUD from an outpatient setting and 55 healthy subjects were evaluated for substance and mental disorders. Plasma samples were obtained to quantify chemokine concentrations [C–C motif (CC), C–X–C motif (CXC), and C–X3–C motif (CX3C) chemokines]. Abstinent AUD patients displayed a high prevalence of comorbid mental disorders (72%) and other substance use disorders (45%). Plasma concentrations of chemokines CXCL12/stromal cell-derived factor-1 (p < 0.001) and CX3CL1/fractalkine (p < 0.05) were lower in AUD patients compared to controls, whereas CCL11/eotaxin-1 concentrations were strongly decreased in female AUD patients (p < 0.001). In the alcohol group, CXCL8 concentrations were increased in patients with liver and pancreas diseases and there was a significant correlation to aspartate transaminase (r = +0.456, p < 0.001) and gamma-glutamyltransferase (r = +0.647, p < 0.001). Focusing on comorbid psychiatric disorders, we distinguish between patients with additional mental disorders (N = 61) and other substance use disorders (N = 38). Only CCL11 concentrations were found to be altered in AUD patients diagnosed with mental disorders (p < 0.01) with a strong main effect of sex. Thus, patients with mood disorders (N = 42) and/or anxiety (N = 16) had lower CCL11 concentrations than non-comorbid patients being more evident in women. The alcohol-induced alterations in circulating chemokines were also explored in preclinical models of alcohol use with male Wistar rats. Rats exposed to repeated ethanol (3 g/kg, gavage) had lower CXCL12 (p < 0.01) concentrations and higher CCL11 concentrations (p < 0.001) relative to vehicle-treated rats. Additionally, the increased CCL11 concentrations in rats exposed to ethanol were enhanced by the prior exposure to restraint stress (p < 0.01). Concordantly, acute ethanol exposure induced changes in CXCL12, CX3CL1, and CCL11 in the same direction to repeated exposure. These results clearly indicate a contribution of specific chemokines to the phenotype of AUD and a strong effect of sex, revealing a link of CCL11 to alcohol and anxiety/stress.

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“…In these studies, higher levels of CCL2 were observed in several brain regions (e.g., hippocampus and cortex) of post-mortem human alcoholics compared to post-mortem human brains from non-alcoholics (Lewohl et al, 2000; He and Crews, 2008). Higher levels of CCL2 were also present in the cerebrospinal fluid (CSF) of alcohol-dependent human subjects compared to non-dependent subjects (Umhau et al, 2014). Studies in experimental animals confirmed that increased expression of CCL2 is produced by alcohol (ethanol) exposure/withdrawal.…”

Section: Introductionmentioning

confidence: 99%

Transgenic mice with increased astrocyte expression of CCL2 show altered behavioral effects of alcohol

2017

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Emerging research provides strong evidence that activation of CNS glial cells occurs in neurological diseases and brain injury and results in elevated production of neuroimmune factors. These factors can contribute to pathophysiological processes that lead to altered CNS function. Recently, studies have also shown that both acute and chronic alcohol consumption can produce activation of CNS glial cells and the production of neuroimmune factors, particularly the chemokine CCL2. The consequences of alcohol-induced increases in CCL2 levels in the CNS have yet to be fully elucidated. Our studies focus on the hypothesis that increased levels of CCL2 in the CNS produce neuroadaptive changes that modify the actions of alcohol on the CNS. We utilized behavioral testing in transgenic mice that express elevated levels of CCL2 to test this hypothesis. The increased level of CCL2 in the transgenic mice involves increased astrocyte expression. Transgenic mice and their non-transgenic littermate controls were subjected to one of two alcohol exposure paradigms, a two-bottle choice alcohol drinking procedure that does not produce alcohol dependence or a chronic intermittent alcohol procedure that produces alcohol dependence. Several behavioral tests were carried out including the Barnes Maze, Y-Maze, cued and contextual conditioned fear test, light-dark transfer, and forced swim test. Comparisons between alcohol naïve, non-dependent, and alcohol dependent CCL2 transgenic and non-tg mice show that elevated levels of CCL2 in the CNS interact with alcohol in tests for alcohol drinking, spatial learning and associative learning.

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Cerebrospinal Fluid Monocyte Chemoattractant Protein‐1 in Alcoholics: Support for a Neuroinflammatory Model of Chronic Alcoholism

Abstract: These preliminary findings are consistent with the hypothesis that neuroinflammation as indexed by CSF MCP-1 is associated with alcohol-induced liver inflammation, as defined by peripheral concentrations of GGT and AST/GOT.

Cited by 38 publications

References 48 publications

Sustained alterations in neuroimmune gene expression after daily, but not intermittent, alcohol exposure

Sustained alterations in neuroimmune gene expression after daily, but not intermittent, alcohol exposure

Plasma Chemokines in Patients with Alcohol Use Disorders: Association of CCL11 (Eotaxin-1) with Psychiatric Comorbidity

Transgenic mice with increased astrocyte expression of CCL2 show altered behavioral effects of alcohol

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