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Innate Immune Signaling and Alcohol Use Disorders

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The Neuropharmacology of Alcohol

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 248))

Abstract

Innate immune signaling is an important feature in the pathology of alcohol use disorders. Alcohol abuse causes persistent innate immune activation in the brain. This is seen in postmortem human alcoholic brain specimens, as well as in primate and rodent models of alcohol consumption. Further, in vitro models of alcohol exposure in neurons and glia also demonstrate innate immune activation. The activation of the innate immune system seems to be important in the development of alcohol use pathology, as anti-immune therapies reduce pathology and ethanol self-administration in rodent models. Further, innate immune activation has been identified in each of the stages of addiction: binge/intoxication, withdrawal/negative affect, and preoccupation/craving. This suggests that innate immune activation may play a role both in the development and maintenance of alcoholic pathology. In this chapter, we discuss the known contributions of innate immune signaling in the pathology of alcohol use disorders, and present potential therapeutic interventions that may be beneficial for alcohol use disorders.

The original version of this chapter was revised. A correction to this chapter is available at https://doi.org/10.1007/164_2018_193.

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Change history

  • 29 January 2019

    In the second paragraph of section 1.3 on line 27, the text appears incorrect as glutamatergic and neurons. It should read as glutamatergic and GABAergic neurons. The original chapter was corrected.

References

  • Agrawal RG et al (2011) Minocycline reduces ethanol drinking. Brain Behav Immun 25(Suppl 1):S165–S169

    CAS  PubMed  PubMed Central  Google Scholar 

  • Alfonso-Loeches S et al (2010) Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. J Neurosci 30(24):8285–8295

    CAS  PubMed  PubMed Central  Google Scholar 

  • Aloe L et al (1999) Learning abilities, NGF and BDNF brain levels in two lines of TNF-alpha transgenic mice, one characterized by neurological disorders, the other phenotypically normal. Brain Res 840(1–2):125–137

    CAS  PubMed  Google Scholar 

  • Arezoomandan R, Haghparast A (2016) Administration of the glial cell modulator, minocycline, in the nucleus accumbens attenuated the maintenance and reinstatement of morphine-seeking behavior. Can J Physiol Pharmacol 94(3):257–264

    CAS  PubMed  Google Scholar 

  • Attarzadeh-Yazdi G, Arezoomandan R, Haghparast A (2014) Minocycline, an antibiotic with inhibitory effect on microglial activation, attenuates the maintenance and reinstatement of methamphetamine-seeking behavior in rat. Prog Neuro-Psychopharmacol Biol Psychiatry 53:142–148

    CAS  Google Scholar 

  • Bachtell R et al (2015) Targeting the toll of drug abuse: the translational potential of toll-like receptor 4. CNS Neurol Disord Drug Targets 14(6):692–699

    CAS  PubMed  PubMed Central  Google Scholar 

  • Badanich KA, Becker HC, Woodward JJ (2011) Effects of chronic intermittent ethanol exposure on orbitofrontal and medial prefrontal cortex-dependent behaviors in mice. Behav Neurosci 125(6):879–891

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bai L et al (2014) Toll-like receptor 4-mediated nuclear factor-kappaB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats. Neurosci Bull 30(6):936–948

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bajo M et al (2015a) Role of the IL-1 receptor antagonist in ethanol-induced regulation of GABAergic transmission in the central amygdala. Brain Behav Immun 45:189–197

    CAS  PubMed  Google Scholar 

  • Bajo M et al (2015b) IL-1 interacts with ethanol effects on GABAergic transmission in the mouse central amygdala. Front Pharmacol 6:49

    PubMed  PubMed Central  Google Scholar 

  • Ballester J, Valentine G, Sofuoglu M (2017) Pharmacological treatments for methamphetamine addiction: current status and future directions. Expert Rev Clin Pharmacol 10(3):305–314

    CAS  PubMed  Google Scholar 

  • Banks WA, Kastin AJ, Gutierrez EG (1994) Penetration of interleukin-6 across the murine blood-brain barrier. Neurosci Lett 179(1–2):53–56

    CAS  PubMed  Google Scholar 

  • Banks WA, Kastin AJ, Broadwell RD (1995) Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation 2(4):241–248

    CAS  PubMed  Google Scholar 

  • Barbierato M et al (2013) Astrocyte-microglia cooperation in the expression of a pro-inflammatory phenotype. CNS Neurol Disord Drug Targets 12(5):608–618

    CAS  PubMed  Google Scholar 

  • Beattie EC et al (2002) Control of synaptic strength by glial TNFalpha. Science 295(5563):2282–2285

    CAS  PubMed  Google Scholar 

  • Bell RL et al (2015) Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence. Addict Biol 20(1):38–42

    CAS  PubMed  Google Scholar 

  • Beynon SB, Walker FR (2012) Microglial activation in the injured and healthy brain: what are we really talking about? Practical and theoretical issues associated with the measurement of changes in microglial morphology. Neuroscience 225:162–171

    CAS  PubMed  Google Scholar 

  • Bhattacharya A, Drevets WC (2017) Role of neuro-immunological factors in the pathophysiology of mood disorders: implications for novel therapeutics for treatment resistant depression. Curr Top Behav Neurosci 31:339–356

    CAS  PubMed  Google Scholar 

  • Bhattacharya A et al (2016) Role of neuro-immunological factors in the pathophysiology of mood disorders. Psychopharmacology 233(9):1623–1636

    CAS  PubMed  Google Scholar 

  • Bi W et al (2011) Rifampicin inhibits microglial inflammation and improves neuron survival against inflammation. Brain Res 1395:12–20

    CAS  PubMed  Google Scholar 

  • Bian C et al (2015) Involvement of CX3CL1/CX3CR1 signaling in spinal long term potentiation. PLoS One 10(3):e0118842

    PubMed  PubMed Central  Google Scholar 

  • Bierhaus A et al (2003) A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci U S A 100(4):1920–1925

    CAS  PubMed  PubMed Central  Google Scholar 

  • Blanc L et al (2013) Gram-positive bacterial lipoglycans based on a glycosylated diacylglycerol lipid anchor are microbe-associated molecular patterns recognized by TLR2. PLoS One 8(11):e81593

    PubMed  PubMed Central  Google Scholar 

  • Blanco AM et al (2005) Involvement of TLR4/type I IL-1 receptor signaling in the induction of inflammatory mediators and cell death induced by ethanol in cultured astrocytes. J Immunol 175(10):6893–6899

    CAS  PubMed  Google Scholar 

  • Blednov YA et al (2005) Perturbation of chemokine networks by gene deletion alters the reinforcing actions of ethanol. Behav Brain Res 165(1):110–125

    CAS  PubMed  PubMed Central  Google Scholar 

  • Blednov YA et al (2011) Activation of inflammatory signaling by lipopolysaccharide produces a prolonged increase of voluntary alcohol intake in mice. Brain Behav Immun 25(Suppl 1):S92–S105

    CAS  PubMed  PubMed Central  Google Scholar 

  • Blednov YA et al (2012) Neuroimmune regulation of alcohol consumption: behavioral validation of genes obtained from genomic studies. Addict Biol 17(1):108–120

    CAS  PubMed  Google Scholar 

  • Blednov YA et al (2014) Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice. Front Neurosci 8:129

    PubMed  PubMed Central  Google Scholar 

  • Borner C, Hollt V, Kraus J (2012) Mechanisms of the inhibition of nuclear factor-kappaB by morphine in neuronal cells. Mol Pharmacol 81(4):587–597

    PubMed  Google Scholar 

  • Bose S, Cho J (2013) Role of chemokine CCL2 and its receptor CCR2 in neurodegenerative diseases. Arch Pharm Res 36(9):1039–1050

    CAS  PubMed  Google Scholar 

  • Breese GR, Overstreet DH, Knapp DJ (2005) Conceptual framework for the etiology of alcoholism: a “kindling”/stress hypothesis. Psychopharmacology 178(4):367–380

    CAS  PubMed  Google Scholar 

  • Breese GR et al (2008) Repeated lipopolysaccharide (LPS) or cytokine treatments sensitize ethanol withdrawal-induced anxiety-like behavior. Neuropsychopharmacology 33(4):867–876

    CAS  PubMed  Google Scholar 

  • Brombacher TM et al (2017) IL-13-mediated regulation of learning and memory. J Immunol 198(7):2681–2688

    CAS  PubMed  Google Scholar 

  • Brubaker SW et al (2015) Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol 33:257–290

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bsibsi M et al (2010) The microtubule regulator stathmin is an endogenous protein agonist for TLR3. J Immunol 184(12):6929–6937

    CAS  PubMed  Google Scholar 

  • Buwitt-Beckmann U et al (2006) TLR1- and TLR6-independent recognition of bacterial lipopeptides. J Biol Chem 281(14):9049–9057

    CAS  PubMed  Google Scholar 

  • Calu DJ et al (2007) Associative encoding in posterior piriform cortex during odor discrimination and reversal learning. Cereb Cortex 17(6):1342–1349

    PubMed  Google Scholar 

  • Cameron JS et al (2007) Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals. J Neurosci 27(47):13033–13041

    CAS  PubMed  PubMed Central  Google Scholar 

  • Caraci F et al (2015) A key role for TGF-beta1 in hippocampal synaptic plasticity and memory. Sci Rep 5:11252

    PubMed  PubMed Central  Google Scholar 

  • Chen G et al (2012) Autophagy is a protective response to ethanol neurotoxicity. Autophagy 8(11):1577–1589

    CAS  PubMed  PubMed Central  Google Scholar 

  • Coleman LG Jr et al (2011) Adolescent binge drinking alters adult brain neurotransmitter gene expression, behavior, brain regional volumes, and neurochemistry in mice. Alcohol Clin Exp Res 35(4):671–688

    CAS  PubMed  PubMed Central  Google Scholar 

  • Coleman LG Jr, Zou J, Crews FT (2017) Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7. J Neuroinflammation 14(1):22

    PubMed  PubMed Central  Google Scholar 

  • Cozzoli DK et al (2016) Functional regulation of PI3K-associated signaling in the accumbens by binge alcohol drinking in male but not female mice. Neuropharmacology 105:164–174

    CAS  PubMed  PubMed Central  Google Scholar 

  • Crews FT, Boettiger CA (2009) Impulsivity, frontal lobes and risk for addiction. Pharmacol Biochem Behav 93(3):237–247

    CAS  PubMed  PubMed Central  Google Scholar 

  • Crews FT, Vetreno RP (2014) Neuroimmune basis of alcoholic brain damage. Int Rev Neurobiol 118:315–357

    PubMed  PubMed Central  Google Scholar 

  • Crews FT, Vetreno RP (2016) Mechanisms of neuroimmune gene induction in alcoholism. Psychopharmacology 233(9):1543–1557

    CAS  PubMed  Google Scholar 

  • Crews F et al (2006) BHT blocks NF-kappaB activation and ethanol-induced brain damage. Alcohol Clin Exp Res 30(11):1938–1949

    CAS  PubMed  Google Scholar 

  • Crews FT, Zou J, Qin L (2011) Induction of innate immune genes in brain create the neurobiology of addiction. Brain Behav Immun 25(Suppl 1):S4–S12

    CAS  PubMed  PubMed Central  Google Scholar 

  • Crews FT et al (2013) High mobility group box 1/toll-like receptor danger signaling increases brain neuroimmune activation in alcohol dependence. Biol Psychiatry 73(7):602–612

    CAS  PubMed  Google Scholar 

  • Crews FT et al (2015) Neuroimmune function and the consequences of alcohol exposure. Alcohol Res 37(2):331–351

    PubMed  PubMed Central  Google Scholar 

  • Crews FT et al (2016) Adolescent alcohol exposure persistently impacts adult neurobiology and behavior. Pharmacol Rev 68(4):1074–1109

    CAS  PubMed  PubMed Central  Google Scholar 

  • Crews FT et al (2017) The role of neuroimmune signaling in alcoholism. Neuropharmacology 122:56–73

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cui C, Shurtleff D, Harris RA (2014) Neuroimmune mechanisms of alcohol and drug addiction. Int Rev Neurobiol 118:1–12

    PubMed  PubMed Central  Google Scholar 

  • Cui C et al (2015) Brain pathways to recovery from alcohol dependence. Alcohol 49(5):435–452

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dantzer R et al (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9(1):46–56

    CAS  PubMed  PubMed Central  Google Scholar 

  • Davis RL, Syapin PJ (2004) Ethanol increases nuclear factor-kappa B activity in human astroglial cells. Neurosci Lett 371(2–3):128–132

    CAS  PubMed  Google Scholar 

  • Dawson DA et al (2008) Age at first drink and the first incidence of adult-onset DSM-IV alcohol use disorders. Alcohol Clin Exp Res 32(12):2149–2160

    PubMed  PubMed Central  Google Scholar 

  • Derecki NC et al (2010) Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 207(5):1067–1080

    CAS  PubMed  PubMed Central  Google Scholar 

  • Di Castro MA et al (2016) The chemokine CXCL16 modulates neurotransmitter release in hippocampal CA1 area. Sci Rep 6:34633

    PubMed  PubMed Central  Google Scholar 

  • Drew PD et al (2015) Pioglitazone blocks ethanol induction of microglial activation and immune responses in the hippocampus, cerebellum, and cerebral cortex in a mouse model of fetal alcohol spectrum disorders. Alcohol Clin Exp Res 39(3):445–454

    CAS  PubMed  PubMed Central  Google Scholar 

  • Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28(3):138–145

    CAS  PubMed  Google Scholar 

  • Fernandez-Lizarbe S, Pascual M, Guerri C (2009) Critical role of TLR4 response in the activation of microglia induced by ethanol. J Immunol 183(7):4733–4744

    CAS  PubMed  Google Scholar 

  • Fernandez-Lizarbe S, Montesinos J, Guerri C (2013) Ethanol induces TLR4/TLR2 association, triggering an inflammatory response in microglial cells. J Neurochem 126(2):261–273

    CAS  PubMed  Google Scholar 

  • Fortier CB et al (2008) Delay discrimination and reversal eyeblink classical conditioning in abstinent chronic alcoholics. Neuropsychology 22(2):196–208

    PubMed  PubMed Central  Google Scholar 

  • Frank MG et al (2007) Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses. Brain Behav Immun 21(1):47–59

    CAS  PubMed  Google Scholar 

  • Frank MG et al (2016) The danger-associated molecular pattern HMGB1 mediates the neuroinflammatory effects of methamphetamine. Brain Behav Immun 51:99–108

    CAS  PubMed  Google Scholar 

  • Franke H (1995) Influence of chronic alcohol treatment on the GFAP-immunoreactivity in astrocytes of the hippocampus in rats. Acta Histochem 97(3):263–271

    CAS  PubMed  Google Scholar 

  • Freeman K et al (2012) Temporal changes in innate immune signals in a rat model of alcohol withdrawal in emotional and cardiorespiratory homeostatic nuclei. J Neuroinflammation 9:97

    CAS  PubMed  PubMed Central  Google Scholar 

  • George FR (1989) The role of arachidonic acid metabolites in mediating ethanol self-administration and intoxication. Ann N Y Acad Sci 559:382–391

    CAS  PubMed  Google Scholar 

  • Ginhoux F et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005):841–845

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ginhoux F et al (2013) Origin and differentiation of microglia. Front Cell Neurosci 7:45

    PubMed  PubMed Central  Google Scholar 

  • Gorina R et al (2011) Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFkappaB signaling, MAPK, and Jak1/Stat1 pathways. Glia 59(2):242–255

    PubMed  Google Scholar 

  • Goshen I et al (2007) A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology 32(8–10):1106–1115

    CAS  PubMed  Google Scholar 

  • Grant BF, Dawson DA (1998) Age of onset of drug use and its association with DSM-IV drug abuse and dependence: results from the National Longitudinal Alcohol Epidemiologic Survey. J Subst Abus 10(2):163–173

    CAS  Google Scholar 

  • Guo ML et al (2015) Cocaine-mediated microglial activation involves the ER stress-autophagy axis. Autophagy 11(7):995–1009

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hanke ML, Kielian T (2011) Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci 121(9):367–387

    CAS  Google Scholar 

  • Hashioka S et al (2015) Interferon-gamma-induced neurotoxicity of human astrocytes. CNS Neurol Disord Drug Targets 14(2):251–256

    CAS  PubMed  Google Scholar 

  • He J, Crews FT (2008) Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp Neurol 210(2):349–358

    CAS  PubMed  Google Scholar 

  • Heberlein A et al (2014) TNF-alpha and IL-6 serum levels: neurobiological markers of alcohol consumption in alcohol-dependent patients? Alcohol 48(7):671–676

    CAS  PubMed  Google Scholar 

  • Hoeffel G et al (2015) C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42(4):665–678

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hu W et al (2011) Inhibition of phosphodiesterase-4 decreases ethanol intake in mice. Psychopharmacology 218(2):331–339

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hutchinson MR et al (2010) Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain Behav Immun 24(1):83–95

    CAS  PubMed  Google Scholar 

  • Irwin MR et al (2009) Tumor necrosis factor antagonism normalizes rapid eye movement sleep in alcohol dependence. Biol Psychiatry 66(2):191–195

    CAS  PubMed  PubMed Central  Google Scholar 

  • Izquierdo A et al (2016) The neural basis of reversal learning: an updated perspective. Neuroscience. https://doi.org/10.1016/j.neuroscience.2016.03.021. [Epub ahead of print]

  • Jackson AC, Rossiter JP, Lafon M (2006) Expression of toll-like receptor 3 in the human cerebellar cortex in rabies, herpes simplex encephalitis, and other neurological diseases. J Neurovirol 12(3):229–234

    CAS  PubMed  Google Scholar 

  • Jacobsen JH, Hutchinson MR, Mustafa S (2016) Drug addiction: targeting dynamic neuroimmune receptor interactions as a potential therapeutic strategy. Curr Opin Pharmacol 26:131–137

    CAS  PubMed  Google Scholar 

  • Jacobsen JHW et al (2018) The efficacy of (+)-naltrexone on alcohol preference and seeking behaviour is dependent on light-cycle. Brain Behav Immun 67:181–193

    CAS  PubMed  Google Scholar 

  • Jang E et al (2013) Phenotypic polarization of activated astrocytes: the critical role of lipocalin-2 in the classical inflammatory activation of astrocytes. J Immunol 191(10):5204–5219

    CAS  PubMed  Google Scholar 

  • Janko C et al (2014) Redox modulation of HMGB1-related signaling. Antioxid Redox Signal 20(7):1075–1085

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jensen CJ, Massie A, De Keyser J (2013) Immune players in the CNS: the astrocyte. J Neuroimmune Pharmacol 8(4):824–839

    PubMed  Google Scholar 

  • Jimenez JL et al (2001) Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-kappaB and nuclear factor of activated T cells activation. J Pharmacol Exp Ther 299(2):753–759

    CAS  PubMed  Google Scholar 

  • Jokisch D et al (2014) Impairments in learning by monetary rewards and alcohol-associated rewards in detoxified alcoholic patients. Alcohol Clin Exp Res 38(7):1947–1954

    PubMed  Google Scholar 

  • June HL et al (2015) CRF-amplified neuronal TLR4/MCP-1 signaling regulates alcohol self-administration. Neuropsychopharmacology 40(6):1549–1559

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kaltschmidt B, Kaltschmidt C (2015) NF-KappaB in long-term memory and structural plasticity in the adult mammalian brain. Front Mol Neurosci 8:69

    PubMed  PubMed Central  Google Scholar 

  • Kane CJ et al (2011) Protection of neurons and microglia against ethanol in a mouse model of fetal alcohol spectrum disorders by peroxisome proliferator-activated receptor-gamma agonists. Brain Behav Immun 25(Suppl 1):S137–S145

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kettenmann H et al (2011) Physiology of microglia. Physiol Rev 91(2):461–553

    CAS  PubMed  Google Scholar 

  • Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77(1):10–18

    CAS  PubMed  Google Scholar 

  • Khairova RA et al (2009) A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. Int J Neuropsychopharmacol 12(4):561–578

    CAS  PubMed  Google Scholar 

  • Khakh BS, Sofroniew MV (2015) Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 18(7):942–952

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim C et al (2013) Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun 4:1562

    PubMed  Google Scholar 

  • Knapp DJ, Crews FT (1999) Induction of cyclooxygenase-2 in brain during acute and chronic ethanol treatment and ethanol withdrawal. Alcohol Clin Exp Res 23(4):633–643

    CAS  PubMed  Google Scholar 

  • Koob GF, Le Moal M (2005) Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction. Nat Neurosci 8(11):1442–1444

    CAS  PubMed  Google Scholar 

  • Koob GF, Volkow ND (2010) Neurocircuitry of addiction. Neuropsychopharmacology 35(1):217–238

    PubMed  Google Scholar 

  • Koob GF, Volkow ND (2016) Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 3(8):760–773

    PubMed  PubMed Central  Google Scholar 

  • Kreisel T et al (2014) Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol Psychiatry 19(6):699–709

    CAS  PubMed  Google Scholar 

  • Lawrimore C, Crews F (2017) Ethanol, TLR3, and TLR4 agonists have unique innate immune responses in neuron-like SH-SY5Y and microglia-like BV2. Alcohol Clin Exp Res 41:939–954

    CAS  PubMed  PubMed Central  Google Scholar 

  • Leclercq S et al (2014) Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependence. Biol Psychiatry 76(9):725–733

    CAS  PubMed  Google Scholar 

  • Lee M, McGeer E, McGeer PL (2013) Neurotoxins released from interferon-gamma-stimulated human astrocytes. Neuroscience 229:164–175

    CAS  PubMed  Google Scholar 

  • Lehmann SM et al (2012a) An unconventional role for miRNA: let-7 activates toll-like receptor 7 and causes neurodegeneration. Nat Neurosci 15(6):827–835

    CAS  PubMed  Google Scholar 

  • Lehmann SM et al (2012b) Extracellularly delivered single-stranded viral RNA causes neurodegeneration dependent on TLR7. J Immunol 189(3):1448–1458

    CAS  PubMed  Google Scholar 

  • Lewohl JM et al (2011) Up-regulation of microRNAs in brain of human alcoholics. Alcohol Clin Exp Res 35(11):1928–1937

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liang Y et al (2014) Toll-like receptor 4 is associated with seizures following ischemia with hyperglycemia. Brain Res 1590:75–84

    CAS  PubMed  Google Scholar 

  • Liddelow SA et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638):481–487

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lim SW et al (2017) Simvastatin therapy in the acute stage of traumatic brain injury attenuates brain trauma-induced depression-like behavior in rats by reducing Neuroinflammation in the hippocampus. Neurocrit Care 26:122–132. https://doi.org/10.1007/s12028-016-0290-6

    Article  CAS  PubMed  Google Scholar 

  • Lippai D et al (2013) Alcohol-induced IL-1beta in the brain is mediated by NLRP3/ASC inflammasome activation that amplifies neuroinflammation. J Leukoc Biol 94(1):171–182

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J et al (2011) Binge alcohol drinking is associated with GABAA alpha2-regulated toll-like receptor 4 (TLR4) expression in the central amygdala. Proc Natl Acad Sci U S A 108(11):4465–4470

    CAS  PubMed  PubMed Central  Google Scholar 

  • Loftis JM, Janowsky A (2014) Neuroimmune basis of methamphetamine toxicity. Int Rev Neurobiol 118:165–197

    PubMed  PubMed Central  Google Scholar 

  • Ma Y et al (2006) Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis. J Cell Biol 175(2):209–215

    CAS  PubMed  PubMed Central  Google Scholar 

  • Madrigal JL et al (2002) Stress-induced increase in extracellular sucrose space in rats is mediated by nitric oxide. Brain Res 938(1–2):87–91

    CAS  PubMed  Google Scholar 

  • Mao XR et al (2009) Unique aspects of transcriptional regulation in neurons--nuances in NFkappaB and Sp1-related factors. J Neuroinflammation 6:16

    PubMed  PubMed Central  Google Scholar 

  • Marciniak E et al (2015) The chemokine MIP-1alpha/CCL3 impairs mouse hippocampal synaptic transmission, plasticity and memory. Sci Rep 5:15862

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maroso M et al (2011) Interleukin-1 type 1 receptor/toll-like receptor signalling in epilepsy: the importance of IL-1beta and high-mobility group box 1. J Intern Med 270(4):319–326

    CAS  PubMed  Google Scholar 

  • Marshall SA et al (2016a) IL-1 receptor signaling in the basolateral amygdala modulates binge-like ethanol consumption in male C57BL/6J mice. Brain Behav Immun 51:258–267

    CAS  PubMed  Google Scholar 

  • Marshall SA, Geil CR, Nixon K (2016b) Prior binge ethanol exposure potentiates the microglial response in a model of alcohol-induced neurodegeneration. Brain Sci 6(2). https://doi.org/10.3390/brainsci6020016

  • Marshall SA, McKnight KH, Blose AK, Lysle DT, Thiele TE (2017) Modulation of binge-like ethanol consumption by IL-10 signaling in the basolateral amygdala. J Neuroimmune Pharmacol 12:249–259. https://doi.org/10.1007/s11481-016-9709-2

    Article  PubMed  Google Scholar 

  • Mayfield J, Ferguson L, Harris RA (2013) Neuroimmune signaling: a key component of alcohol abuse. Curr Opin Neurobiol 23(4):513–520

    CAS  PubMed  PubMed Central  Google Scholar 

  • McCarthy GM et al (2017) Chronic ethanol consumption: role of TLR3/TRIF-dependent signaling. Addict Biol epub ahead of print

    Google Scholar 

  • Montesinos J et al (2015) TLR4 elimination prevents synaptic and myelin alterations and long-term cognitive dysfunctions in adolescent mice with intermittent ethanol treatment. Brain Behav Immun 45:233–244. https://doi.org/10.1016/j.bbi.2014.11.015

    Article  CAS  PubMed  Google Scholar 

  • Montesinos J, Alfonso-Loeches S, Guerri C (2016) Impact of the innate immune response in the actions of ethanol on the central nervous system. Alcohol Clin Exp Res 40(11):2260–2270

    CAS  PubMed  Google Scholar 

  • Montesinos J, Gil A, Guerri C (2017) Nalmefene prevents alcohol-induced neuroinflammation and alcohol drinking preference in adolescent female mice: role of TLR4. Alcohol Clin Exp Res (41)7:1257–1270

    Google Scholar 

  • Most D, Ferguson L, Harris RA (2014) Molecular basis of alcoholism. Handb Clin Neurol 125:89–111

    PubMed  PubMed Central  Google Scholar 

  • Muller S, Ronfani L, Bianchi ME (2004) Regulated expression and subcellular localization of HMGB1, a chromatin protein with a cytokine function. J Intern Med 255(3):332–343

    CAS  PubMed  Google Scholar 

  • Mulligan MK et al (2006) Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis. Proc Natl Acad Sci U S A 103(16):6368–6373

    CAS  PubMed  PubMed Central  Google Scholar 

  • Narayanan KB, Park HH (2015) Toll/interleukin-1 receptor (TIR) domain-mediated cellular signaling pathways. Apoptosis 20(2):196–209

    CAS  PubMed  Google Scholar 

  • Neupane SP (2016) Neuroimmune interface in the comorbidity between alcohol use disorder and major depression. Front Immunol 7:655

    PubMed  PubMed Central  Google Scholar 

  • Northcutt AL et al (2015) DAT isn’t all that: cocaine reward and reinforcement require toll-like receptor 4 signaling. Mol Psychiatry 20(12):1525–1537

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nunez YO et al (2013) Positively correlated miRNA-mRNA regulatory networks in mouse frontal cortex during early stages of alcohol dependence. BMC Genomics 14:725

    CAS  PubMed  PubMed Central  Google Scholar 

  • Obernier JA et al (2002) Cognitive deficits and CNS damage after a 4-day binge ethanol exposure in rats. Pharmacol Biochem Behav 72(3):521–532

    CAS  PubMed  Google Scholar 

  • Okuma Y et al (2014) Glycyrrhizin inhibits traumatic brain injury by reducing HMGB1-RAGE interaction. Neuropharmacology 85:18–26

    CAS  PubMed  Google Scholar 

  • Okun E et al (2010) Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis. Proc Natl Acad Sci U S A 107(35):15625–15630

    CAS  PubMed  PubMed Central  Google Scholar 

  • Okvist A et al (2007) Neuroadaptations in human chronic alcoholics: dysregulation of the NF-kappaB system. PLoS One 2(9):e930

    PubMed  PubMed Central  Google Scholar 

  • Park JS et al (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 279(9):7370–7377

    CAS  PubMed  Google Scholar 

  • Park CK et al (2014) Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1. Neuron 82(1):47–54

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pascual M et al (2007) Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats. Eur J Neurosci 25(2):541–550

    PubMed  Google Scholar 

  • Pascual M et al (2011) Impact of TLR4 on behavioral and cognitive dysfunctions associated with alcohol-induced neuroinflammatory damage. Brain Behav Immun 25(Suppl 1):S80–S91

    CAS  PubMed  Google Scholar 

  • Pekny M, Pekna M (2014) Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol Rev 94(4):1077–1098

    PubMed  Google Scholar 

  • Periyasamy P, Guo ML, Buch S (2016) Cocaine induces astrocytosis through ER stress-mediated activation of autophagy. Autophagy 12(8):1310–1329

    CAS  PubMed  PubMed Central  Google Scholar 

  • Periyasamy P et al (2017) Cocaine-mediated downregulation of miR-124 activates microglia by targeting KLF4 and TLR4 signaling. Mol Neurobiol Epub ahead of print

    Google Scholar 

  • Pla A, Pascual M, Guerri C (2016) Autophagy constitutes a protective mechanism against ethanol toxicity in mouse astrocytes and neurons. PLoS One 11(4):e0153097

    PubMed  PubMed Central  Google Scholar 

  • Plane JM et al (2010) Prospects for minocycline neuroprotection. Arch Neurol 67(12):1442–1448

    PubMed  PubMed Central  Google Scholar 

  • Prieto GA, Cotman CW (2017) Cytokines and cytokine networks target neurons to modulate long-term potentiation. Cytokine Growth Factor Rev 34:27–33

    CAS  PubMed  PubMed Central  Google Scholar 

  • Prieto GA et al (2015) Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1beta in the aged hippocampus. Proc Natl Acad Sci U S A 112(36):E5078–E5087

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qin L, Crews FT (2012a) NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration. J Neuroinflammation 9:5

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qin L, Crews FT (2012b) Chronic ethanol increases systemic TLR3 agonist-induced neuroinflammation and neurodegeneration. J Neuroinflammation 9:130

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qin L et al (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55(5):453–462

    PubMed  PubMed Central  Google Scholar 

  • Qin L et al (2008) Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. J Neuroinflammation 5:10

    PubMed  PubMed Central  Google Scholar 

  • Ray LA et al (2014) Opportunities for the development of neuroimmune therapies in addiction. Int Rev Neurobiol 118:381–401

    PubMed  Google Scholar 

  • Reissner KJ, Kalivas PW (2010) Using glutamate homeostasis as a target for treating addictive disorders. Behav Pharmacol 21(5–6):514–522

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ripley TL et al (2015) The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice. Psychopharmacology 232(18):3431–3441

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rostene W, Kitabgi P, Parsadaniantz SM (2007) Chemokines: a new class of neuromodulator? Nat Rev Neurosci 8(11):895–903

    CAS  PubMed  Google Scholar 

  • Rubio-Araiz A et al (2017) Disruption of blood-brain barrier integrity in postmortem alcoholic brain: preclinical evidence of TLR4 involvement from a binge-like drinking model. Addict Biol 22:1103–1116. https://doi.org/10.1111/adb.12376

    Article  CAS  PubMed  Google Scholar 

  • Salter MW, Stevens B (2017) Microglia emerge as central players in brain disease. Nat Med 23(9):1018–1027

    CAS  PubMed  Google Scholar 

  • Schoenbaum G et al (2004) Cocaine-experienced rats exhibit learning deficits in a task sensitive to orbitofrontal cortex lesions. Eur J Neurosci 19(7):1997–2002

    PubMed  Google Scholar 

  • Serramia MJ, Munoz-Fernandez MA, Alvarez S (2015) HIV-1 increases TLR responses in human primary astrocytes. Sci Rep 5:17887

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sheng J, Ruedl C, Karjalainen K (2015) Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells. Immunity 43(2):382–393

    CAS  PubMed  Google Scholar 

  • Sironi L et al (2006) Activation of NF-kB and ERK1/2 after permanent focal ischemia is abolished by simvastatin treatment. Neurobiol Dis 22(2):445–451

    CAS  PubMed  Google Scholar 

  • Stalnaker TA et al (2009) Neural substrates of cognitive inflexibility after chronic cocaine exposure. Neuropharmacology 56(Suppl 1):63–72

    CAS  PubMed  Google Scholar 

  • Storer PD et al (2005) Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: implications for multiple sclerosis. J Neuroimmunol 161(1–2):113–122

    CAS  PubMed  Google Scholar 

  • Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40(2):133–139

    PubMed  Google Scholar 

  • Sugimura T, Yoshimura Y, Komatsu Y (2015) TNFalpha is required for the production of T-type Ca(2+) channel-dependent long-term potentiation in visual cortex. Neurosci Res 96:37–44

    CAS  PubMed  Google Scholar 

  • Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140(6):805–820

    CAS  PubMed  Google Scholar 

  • Tancredi V et al (1992) Tumor necrosis factor alters synaptic transmission in rat hippocampal slices. Neurosci Lett 146(2):176–178

    CAS  PubMed  Google Scholar 

  • Theberge FR et al (2013) Effect of chronic delivery of the toll-like receptor 4 antagonist (+)-naltrexone on incubation of heroin craving. Biol Psychiatry 73(8):729–737

    CAS  PubMed  PubMed Central  Google Scholar 

  • Townshend JM, Duka T (2003) Mixed emotions: alcoholics’ impairments in the recognition of specific emotional facial expressions. Neuropsychologia 41(7):773–782

    CAS  PubMed  Google Scholar 

  • Tynan RJ et al (2010) Chronic stress alters the density and morphology of microglia in a subset of stress-responsive brain regions. Brain Behav Immun 24(7):1058–1068

    CAS  PubMed  Google Scholar 

  • Vabulas RM et al (2002) The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the toll-like receptor 2/4 pathway. J Biol Chem 277(23):20847–20853

    CAS  PubMed  Google Scholar 

  • Valenta JP, Gonzales RA (2016) Chronic intracerebroventricular infusion of monocyte chemoattractant protein-1 leads to a persistent increase in sweetened ethanol consumption during operant self-administration but does not influence sucrose consumption in long-Evans rats. Alcohol Clin Exp Res 40(1):187–195

    CAS  PubMed  Google Scholar 

  • Valles SL et al (2004) Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. Brain Pathol 14(4):365–371

    CAS  PubMed  Google Scholar 

  • Vetreno RP, Crews FT (2012) Adolescent binge drinking increases expression of the danger signal receptor agonist HMGB1 and toll-like receptors in the adult prefrontal cortex. Neuroscience 226:475–488

    CAS  PubMed  Google Scholar 

  • Vetreno RP, Crews FT (2014) Current hypotheses on the mechanisms of alcoholism. Handb Clin Neurol 125:477–497

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vetreno RP, Qin L, Crews FT (2013) Increased receptor for advanced glycation end product expression in the human alcoholic prefrontal cortex is linked to adolescent drinking. Neurobiol Dis 59:52–62

    CAS  PubMed  PubMed Central  Google Scholar 

  • Volkow ND, Koob GF, McLellan AT (2016) Neurobiologic advances from the brain disease model of addiction. N Engl J Med 374(4):363–371

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wagley Y et al (2013) Inhibition of c-Jun NH2-terminal kinase stimulates mu opioid receptor expression via p38 MAPK-mediated nuclear NF-kappaB activation in neuronal and non-neuronal cells. Biochim Biophys Acta 1833(6):1476–1488

    CAS  PubMed  PubMed Central  Google Scholar 

  • Walter TJ, Crews FT (2017) Microglial depletion alters the brain neuroimmune response to acute binge ethanol withdrawal. J Neuroinflammation 14(1):86

    PubMed  PubMed Central  Google Scholar 

  • Wang X et al (2013) Rifampin inhibits toll-like receptor 4 signaling by targeting myeloid differentiation protein 2 and attenuates neuropathic pain. FASEB J 27(7):2713–2722

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X et al (2016) Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4. Br J Pharmacol 173(5):856–869

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ward RJ et al (1996) Identification of the nuclear transcription factor NFkappaB in rat after in vivo ethanol administration. FEBS Lett 389(2):119–122

    CAS  PubMed  Google Scholar 

  • Ward RJ et al (2009) Neuro-inflammation induced in the hippocampus of ‘binge drinking’ rats may be mediated by elevated extracellular glutamate content. J Neurochem 111(5):1119–1128

    CAS  PubMed  Google Scholar 

  • Weber MD et al (2015) Stress induces the danger-associated molecular pattern HMGB-1 in the hippocampus of male Sprague Dawley rats: a priming stimulus of microglia and the NLRP3 inflammasome. J Neurosci 35(1):316–324

    PubMed  PubMed Central  Google Scholar 

  • Weissenborn R, Duka T (2003) Acute alcohol effects on cognitive function in social drinkers: their relationship to drinking habits. Psychopharmacology 165(3):306–312

    CAS  PubMed  Google Scholar 

  • Whitman BA et al (2013) The cytokine mRNA increase induced by withdrawal from chronic ethanol in the sterile environment of brain is mediated by CRF and HMGB1 release. Alcohol Clin Exp Res 37(12):2086–2097

    CAS  PubMed  Google Scholar 

  • Wohleb ES et al (2011) Beta-adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J Neurosci 31(17):6277–6288

    CAS  PubMed  PubMed Central  Google Scholar 

  • Worley MJ et al (2016) Ibudilast attenuates subjective effects of methamphetamine in a placebo-controlled inpatient study. Drug Alcohol Depend 162:245–250

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yanai H et al (2009) HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature 462(7269):99–103

    CAS  PubMed  Google Scholar 

  • Yelamanchili SV et al (2015) MiR-21 in extracellular vesicles leads to neurotoxicity via TLR7 signaling in SIV neurological disease. PLoS Pathog 11(7):e1005032

    PubMed  PubMed Central  Google Scholar 

  • Yirmiya R, Goshen I (2011) Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25(2):181–213

    CAS  PubMed  Google Scholar 

  • Zhang B et al (2015) Azithromycin drives alternative macrophage activation and improves recovery and tissue sparing in contusion spinal cord injury. J Neuroinflammation 12:218

    PubMed  PubMed Central  Google Scholar 

  • Zhu CB et al (2010) Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology 35(13):2510–2520

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zou JY, Crews FT (2005) TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition. Brain Res 1034(1–2):11–24

    CAS  PubMed  Google Scholar 

  • Zou J, Crews F (2006) CREB and NF-kappaB transcription factors regulate sensitivity to excitotoxic and oxidative stress induced neuronal cell death. Cell Mol Neurobiol 26(4–6):385–405

    CAS  PubMed  Google Scholar 

  • Zou J, Crews F (2010) Induction of innate immune gene expression cascades in brain slice cultures by ethanol: key role of NF-kappaB and proinflammatory cytokines. Alcohol Clin Exp Res 34(5):777–789

    CAS  PubMed  Google Scholar 

  • Zou J, Crews FT (2012) Inflammasome-IL-1beta signaling mediates ethanol inhibition of hippocampal neurogenesis. Front Neurosci 6:77

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zou JY, Crews FT (2014) Release of neuronal HMGB1 by ethanol through decreased HDAC activity activates brain neuroimmune signaling. PLoS One 9(2):e87915

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank the National Institute on Alcohol Abuse and Alcoholism for its support through the Neurobiology of Adolescent Drinking in Adulthood (NADIA) consortium (AA020024, AA020023), the Bowles Center for Alcohol Studies (AA011605), the U54 collaborative partnership between NCCU and UNC (AA019767), the K08 award program (AA024829), and the Monkey Alcohol and Tissue Research Resource (MATRR-R24 AA019431).

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Authors and Affiliations

  1. Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

    Leon G. Coleman Jr. & Fulton T. Crews

  2. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Leon G. Coleman Jr. & Fulton T. Crews

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  1. Leon G. Coleman Jr.
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  2. Fulton T. Crews
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Correspondence to Leon G. Coleman Jr. .

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Editors and Affiliations

  1. Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA

    Kathleen A. Grant

  2. Laboratory for Integrative Neuroscience, National Institutes of Health, Bethesda, MD, USA

    David M. Lovinger

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Coleman, L.G., Crews, F.T. (2018). Innate Immune Signaling and Alcohol Use Disorders. In: Grant, K., Lovinger, D. (eds) The Neuropharmacology of Alcohol . Handbook of Experimental Pharmacology, vol 248. Springer, Cham. https://doi.org/10.1007/164_2018_92

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