Limits...
Neuroimmune Function and the Consequences of Alcohol Exposure

View Article: PubMed Central

ABSTRACT

Induction of neuroimmune genes by binge drinking increases neuronal excitability and oxidative stress, contributing to the neurobiology of alcohol dependence and causing neurodegeneration. Ethanol exposure activates signaling pathways featuring high-mobility group box 1 and Toll-like receptor 4 (TLR4), resulting in induction of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells, which regulates expression of several cytokine genes involved in innate immunity, and its target genes. This leads to persistent neuroimmune responses to ethanol that stimulate TLRs and/or certain glutamate receptors (i.e., N-methyl-d-aspartate receptors). Alcohol also alters stress responses, causing elevation of peripheral cytokines, which further sensitize neuroimmune responses to ethanol. Neuroimmune signaling and glutamate excitotoxicity are linked to alcoholic neurodegeneration. Models of alcohol abuse have identified significant frontal cortical degeneration and loss of hippocampal neurogenesis, consistent with neuroimmune activation pathology contributing to these alcohol-induced, long-lasting changes in the brain. These alcohol-induced long-lasting increases in brain neuroimmune-gene expression also may contribute to the neurobiology of alcohol use disorder.

No MeSH data available.


Related in: MedlinePlus

Neuroimmune signaling integrates central nervous system (CNS) responses to alcohol and stress. (Left) Stressors activate the body’s stress response system, which is comprised of the hypothalamus, pituitary gland, and adrenal glands (i.e., HPA axis) as well as the stress hormones they produce (e.g., adrenocorticotropic hormone and glucocorticoids). Stress also activates the sympathetic nervous system, which secretes catecholamines. These hormones act on various organs and tissues that are part of the immune system. In response, immune cells secrete cytokines that via the blood are transported to the brain. There, these cytokines lead to brain neuroimmune-gene induction that sensitizes stress-response pathways. At the same time, the immune system communicates with the CNS through sensory (afferent) nerves that activate the brain in response to stressful stimuli. This communication pathway involves particularly the vagus nerve and the nucleus tractus solitarius in the brain stem. (Right) Alcohol influences neuroimmune signaling via its effects on the gastrointestinal tract. Consumed ethanol enters the stomach and gut and makes them “leaky” by inducing the release of high-mobility group box 1 (HMGB1), which in turn activates Toll-like receptor 4 (TLR4) in the gut. As a result, bacterial products such as lipopolysaccharide (LPS) can enter the blood and reach the liver. Both LPS and ethanol (which also reaches the liver via the circulation) contribute to inflammatory reactions in the liver, which lead to release of tumor necrosis factor-alpha (TNF-α) and other proinflammatory cytokines from the liver. These proinflammatory cytokines in the blood enter the brain and increase neuroimmune-gene expression. Chronic ethanol also increases expression of HMGB1–TLR4 signaling in the brain, leading to persistent and progressive increases in neuroimmune-gene expression in the brain.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4590627&req=5

f6-arcr-37-2-331: Neuroimmune signaling integrates central nervous system (CNS) responses to alcohol and stress. (Left) Stressors activate the body’s stress response system, which is comprised of the hypothalamus, pituitary gland, and adrenal glands (i.e., HPA axis) as well as the stress hormones they produce (e.g., adrenocorticotropic hormone and glucocorticoids). Stress also activates the sympathetic nervous system, which secretes catecholamines. These hormones act on various organs and tissues that are part of the immune system. In response, immune cells secrete cytokines that via the blood are transported to the brain. There, these cytokines lead to brain neuroimmune-gene induction that sensitizes stress-response pathways. At the same time, the immune system communicates with the CNS through sensory (afferent) nerves that activate the brain in response to stressful stimuli. This communication pathway involves particularly the vagus nerve and the nucleus tractus solitarius in the brain stem. (Right) Alcohol influences neuroimmune signaling via its effects on the gastrointestinal tract. Consumed ethanol enters the stomach and gut and makes them “leaky” by inducing the release of high-mobility group box 1 (HMGB1), which in turn activates Toll-like receptor 4 (TLR4) in the gut. As a result, bacterial products such as lipopolysaccharide (LPS) can enter the blood and reach the liver. Both LPS and ethanol (which also reaches the liver via the circulation) contribute to inflammatory reactions in the liver, which lead to release of tumor necrosis factor-alpha (TNF-α) and other proinflammatory cytokines from the liver. These proinflammatory cytokines in the blood enter the brain and increase neuroimmune-gene expression. Chronic ethanol also increases expression of HMGB1–TLR4 signaling in the brain, leading to persistent and progressive increases in neuroimmune-gene expression in the brain.

Mentions: Alcohol has a potent activating effect on the HPA axis as well as on neuroimmune signaling; therefore, these effects may integrate the responses of the central nervous system (CNS) to alcohol and stress (figure 6). For example, TNF-α, IL-1β, and IL-6 act upon the HPA axis and SNS, both directly via local effects and indirectly via the CNS (Besedovsky and del Rey 1996; Pickering et al. 2005; Wilder 1995). Furthermore, CRH has a variety of complex effects on immune cells (Elenkov et al. 1999) and modulates immune/inflammatory responses through receptor-mediated actions of glucocorticoids on anti-inflammatory target immune cells (Tsigos and Chrousos 2002). In contrast, elevated glucocorticoid levels in the prefrontal cortex are proinflammatory, potentiating LPS–TLR4 activation of NF-κB and other proinflammatory signals (Munhoz et al. 2010). The neuro-transmitter norepinephrine that is released by SNS activation also disturbs inflammatory cytokine networks and innate immune-cell function. Similarly, the hypothalamic peptide β-endorphin (BEP), whose release is stimulated by CRH during HPA activation, can inhibit stress-hormone production and activate peripheral immune functions (Sarkar and Zhang 2013). All of these findings suggest that the stress–HPA axis, commonly thought to involve anti-inflammatory glucocorticoid actions, also contributes to stress–alcohol responses in the brain that can increase proinflammatory HMGB1–TLR–cytokine signaling.


Neuroimmune Function and the Consequences of Alcohol Exposure
Neuroimmune signaling integrates central nervous system (CNS) responses to alcohol and stress. (Left) Stressors activate the body’s stress response system, which is comprised of the hypothalamus, pituitary gland, and adrenal glands (i.e., HPA axis) as well as the stress hormones they produce (e.g., adrenocorticotropic hormone and glucocorticoids). Stress also activates the sympathetic nervous system, which secretes catecholamines. These hormones act on various organs and tissues that are part of the immune system. In response, immune cells secrete cytokines that via the blood are transported to the brain. There, these cytokines lead to brain neuroimmune-gene induction that sensitizes stress-response pathways. At the same time, the immune system communicates with the CNS through sensory (afferent) nerves that activate the brain in response to stressful stimuli. This communication pathway involves particularly the vagus nerve and the nucleus tractus solitarius in the brain stem. (Right) Alcohol influences neuroimmune signaling via its effects on the gastrointestinal tract. Consumed ethanol enters the stomach and gut and makes them “leaky” by inducing the release of high-mobility group box 1 (HMGB1), which in turn activates Toll-like receptor 4 (TLR4) in the gut. As a result, bacterial products such as lipopolysaccharide (LPS) can enter the blood and reach the liver. Both LPS and ethanol (which also reaches the liver via the circulation) contribute to inflammatory reactions in the liver, which lead to release of tumor necrosis factor-alpha (TNF-α) and other proinflammatory cytokines from the liver. These proinflammatory cytokines in the blood enter the brain and increase neuroimmune-gene expression. Chronic ethanol also increases expression of HMGB1–TLR4 signaling in the brain, leading to persistent and progressive increases in neuroimmune-gene expression in the brain.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4590627&req=5

f6-arcr-37-2-331: Neuroimmune signaling integrates central nervous system (CNS) responses to alcohol and stress. (Left) Stressors activate the body’s stress response system, which is comprised of the hypothalamus, pituitary gland, and adrenal glands (i.e., HPA axis) as well as the stress hormones they produce (e.g., adrenocorticotropic hormone and glucocorticoids). Stress also activates the sympathetic nervous system, which secretes catecholamines. These hormones act on various organs and tissues that are part of the immune system. In response, immune cells secrete cytokines that via the blood are transported to the brain. There, these cytokines lead to brain neuroimmune-gene induction that sensitizes stress-response pathways. At the same time, the immune system communicates with the CNS through sensory (afferent) nerves that activate the brain in response to stressful stimuli. This communication pathway involves particularly the vagus nerve and the nucleus tractus solitarius in the brain stem. (Right) Alcohol influences neuroimmune signaling via its effects on the gastrointestinal tract. Consumed ethanol enters the stomach and gut and makes them “leaky” by inducing the release of high-mobility group box 1 (HMGB1), which in turn activates Toll-like receptor 4 (TLR4) in the gut. As a result, bacterial products such as lipopolysaccharide (LPS) can enter the blood and reach the liver. Both LPS and ethanol (which also reaches the liver via the circulation) contribute to inflammatory reactions in the liver, which lead to release of tumor necrosis factor-alpha (TNF-α) and other proinflammatory cytokines from the liver. These proinflammatory cytokines in the blood enter the brain and increase neuroimmune-gene expression. Chronic ethanol also increases expression of HMGB1–TLR4 signaling in the brain, leading to persistent and progressive increases in neuroimmune-gene expression in the brain.
Mentions: Alcohol has a potent activating effect on the HPA axis as well as on neuroimmune signaling; therefore, these effects may integrate the responses of the central nervous system (CNS) to alcohol and stress (figure 6). For example, TNF-α, IL-1β, and IL-6 act upon the HPA axis and SNS, both directly via local effects and indirectly via the CNS (Besedovsky and del Rey 1996; Pickering et al. 2005; Wilder 1995). Furthermore, CRH has a variety of complex effects on immune cells (Elenkov et al. 1999) and modulates immune/inflammatory responses through receptor-mediated actions of glucocorticoids on anti-inflammatory target immune cells (Tsigos and Chrousos 2002). In contrast, elevated glucocorticoid levels in the prefrontal cortex are proinflammatory, potentiating LPS–TLR4 activation of NF-κB and other proinflammatory signals (Munhoz et al. 2010). The neuro-transmitter norepinephrine that is released by SNS activation also disturbs inflammatory cytokine networks and innate immune-cell function. Similarly, the hypothalamic peptide β-endorphin (BEP), whose release is stimulated by CRH during HPA activation, can inhibit stress-hormone production and activate peripheral immune functions (Sarkar and Zhang 2013). All of these findings suggest that the stress–HPA axis, commonly thought to involve anti-inflammatory glucocorticoid actions, also contributes to stress–alcohol responses in the brain that can increase proinflammatory HMGB1–TLR–cytokine signaling.

View Article: PubMed Central

ABSTRACT

Induction of neuroimmune genes by binge drinking increases neuronal excitability and oxidative stress, contributing to the neurobiology of alcohol dependence and causing neurodegeneration. Ethanol exposure activates signaling pathways featuring high-mobility group box 1 and Toll-like receptor 4 (TLR4), resulting in induction of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells, which regulates expression of several cytokine genes involved in innate immunity, and its target genes. This leads to persistent neuroimmune responses to ethanol that stimulate TLRs and/or certain glutamate receptors (i.e., N-methyl-d-aspartate receptors). Alcohol also alters stress responses, causing elevation of peripheral cytokines, which further sensitize neuroimmune responses to ethanol. Neuroimmune signaling and glutamate excitotoxicity are linked to alcoholic neurodegeneration. Models of alcohol abuse have identified significant frontal cortical degeneration and loss of hippocampal neurogenesis, consistent with neuroimmune activation pathology contributing to these alcohol-induced, long-lasting changes in the brain. These alcohol-induced long-lasting increases in brain neuroimmune-gene expression also may contribute to the neurobiology of alcohol use disorder.

No MeSH data available.


Related in: MedlinePlus