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The Role of Neuroimmune Signaling in Alcoholism

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The Role of Neuroimmune Signaling in Alcoholism Neuropharmacology 122 (2017) 56e73 Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm Invited review The role of neuroimmune signaling in alcoholism * Fulton T. Crews, Colleen J. Lawrimore, T. Jordan Walter, Leon G. Coleman Jr. University of North Carolina, Chapel Hill School of Medicine, Bowles Center for Alcohol Studies, CB# 7178 UNC-CH, Chapel Hill, NC 27599, USA article info abstract Article history: Alcohol consumption and stress increase brain levels of known innate immune signaling molecules. Received 14 September 2016 Microglia, the innate immune cells of the brain, and neurons respond to alcohol, signaling through Toll- Received in revised form like receptors (TLRs), high-mobility group box 1 (HMGB1), miRNAs, pro-inflammatory cytokines and 24 January 2017 their associated receptors involved in signaling between microglia, other glia and neurons. Repeated Accepted 29 January 2017 cycles of alcohol and stress cause a progressive, persistent induction of HMGB1, miRNA and TLR receptors Available online 1 February 2017 in brain that appear to underlie the progressive and persistent loss of behavioral control, increased impulsivity and anxiety, as well as craving, coupled with increasing ventral striatal responses that Chemical compounds studied in this article: Minocycline (PubChem CID: 54675783) promote reward seeking behavior and increase risk of developing alcohol use disorders. Studies fl Rapamycin (PubChem CID: 5284616) employing anti-oxidant, anti-in ammatory, anti-depressant, and innate immune antagonists further link Azithromycin (PubChem CID: 447043) innate immune gene expression to addiction-like behaviors. Innate immune molecules are novel targets Rifampin (PubChem CID: 5381226) for addiction and affective disorders therapies. Indomethacin (PubChem CID: 3715) This article is part of the Special Issue entitled “Alcoholism”. Simvastatin (PubChem CID: 54454) © 2017 Elsevier Ltd. All rights reserved. Glycyrrhizin (PubChem CID: 14982) Pioglitazone (PubChem CID: 4829) Ibudilast (PubChem CID: 3671) Naltrexone (PubChem CID: 5360515) Keywords: HMGB1 TLR Cytokines miRNA-let-7 Alcohol Addiction Contents 1. Introduction . ........................ 57 2. Alcohol and stress, microglia and neuroimmune signaling . ........................ 57 3. Sensitization of glia in the stressed and addicted brain . ........................ 58 4. Stress, inflammation and affective disorders . ........................ 59 5. Innate immune molecules mimic addiction-like behavior . .. ........................ 61 6. HMGB1, Toll-like receptors and innate immune signaling in the brain . ........................ 62 7. TLR4 - a key brain receptor involved in ethanol induced neuropathology . ........................ 63 8. Induction of innate immune genes, and miRNA . ........................ 64 9. Autocrine and paracrine processes amplify NF-kB innate immune gene induction . ........................ 65 10. New treatments strategies based on immune pharmacology . ........................ 65 11. Neuroimmune basis of addiction . .................................................. 67 Acknowledgments . ...................................................68 References . ...................................................68 * Corresponding author. E-mail address: [email protected] (L.G. Coleman). http://dx.doi.org/10.1016/j.neuropharm.2017.01.031 0028-3908/© 2017 Elsevier Ltd. All rights reserved. F.T. Crews et al. / Neuropharmacology 122 (2017) 56e73 57 1. Introduction of this system leads to progressive and persistent loss of behavioral control, increased impulsivity and anxiety, as well as negative affect Neuroimmune signaling is emerging as a contributor to the and craving coupled with increasing ventral striatal responses that development of alcohol use disorders. Alcohol consumption and promote reward seeking behavior and increase risk of developing stress increase brain levels of known innate immune signaling alcohol use disorders. Studies employing anti-oxidant, anti-in- molecules. Microglia, the innate immune cells of the brain, play an flammatory, anti-depressant, and innate immune antagonists important role in brain development and function. As mesodermal further link innate immune gene expression to addiction-like be- tissue specific monocytes, microglia express signaling molecules haviors. In this review we discuss both preclinical rodent and hu- first characterized as “acute phase proteins” that increase in blood man studies that examine the role of neuroimmune signaling in rapidly in response to infections. More recently, Toll-like receptors alcoholism. Unless otherwise noted the presented studies were (TLRs), members of a superfamily of receptors, i.e. - interleukin-1 performed in rodents. From these studies, we surmise that innate receptor/toll-like receptor superfamily, were found to initiate pro- immune molecules are novel targets for addiction and affective inflammatory responses to infectious agents by sensing large disorders therapies. molecules with lipid, sugar, protein and nucleic acid components. Pro-inflammatory cytokines and their associated receptors share 2. Alcohol and stress, microglia and neuroimmune signaling complex signaling pathways with TLRs that converge upon NF-kB, a key innate immune transcription factor in monocyte-like cells, and Repeated cycles of alcohol, drugs of abuse and stress interact, other transcription factors regulated by TLR-kinase cascades. contributing to a progressive sequence of stages leading to addic- Recent studies in brain, which is generally sterile, indicate endog- tion (Volkow et al., 2016). Alcohol, drugs of abuse and stress also enous TLR agonists, i.e. danger-associated molecular patterns trigger neuroinflammatory responses. Inflammation may have (DAMPs), represent important signaling systems between micro- beneficial or maladaptive consequences on brain function (Fig. 1). glia, other glia and neurons. Further, emerging studies find cyto- Physical stressors, such as injury and infection, increase pro- kines and DAMPs may signal directly between neurons. High- inflammatory cytokines and other leukocyte derived proteins and mobility group box 1 (HMGB1) is a cytokine-like molecule highly prostaglandins as part of the acute inflammatory phase response. expressed in neurons that can directly activate TLRs as well as Stressor-induced inflammation also triggers adaptive behavioral enhancing responses at other pro-inflammatory receptors. Alcohol- changes known as “sickness behavior.” Sickness behavior includes and stress-induced increases in Toll-like receptors, and other neu- social withdrawal, decreased activity, somnolence/sleepiness, roimmune signaling molecules in brain sensitize the brain to anhedonia, etc. that help to conserve energy and facilitate recovery further innate immune gene induction, resulting in progressive and (Dantzer et al., 2008). Interestingly, even psychological stressors persistent increases in HMGB1 and TLR signaling as evidenced by (e.g. e social stress) can cause inflammation (Steptoe et al., 2007). prefrontal cortical expression levels correlating with lifetime The acute pro-inflammatory response, often referred to as Th1, alcohol consumption across alcoholic and moderate drinking con- includes signals that activate a delayed wound healing and cell trols (Crews et al., 2013). Mechanistic studies of epilepsy find growth through “anti-inflammatory” Th2 innate immune signaling neuronal firing results in the rapid release of HMGB1 and IL-1b molecules. While the benefit of the Th1 to Th2 progression preceding the seizure, inducing changes in excitatory receptors that following trauma or infection may be apparent, what happens in sensitize neurons to excitation, lowering seizure threshold and brain is poorly understood. Therefore, both physical and psycho- contributing to the “kindling” progressive increase in seizure fre- logical stressors may enhance inflammation, initiating molecular quency and severity with each event (Maroso et al., 2011). Although and behavioral changes that facilitate recovery. While stress and different brain regions and circuits distinguish addiction from ep- inflammation can lead to the adaptive response of sickness ilepsy, HMGB1 and TLR signaling and cycles of stress and drug behavior, intense or chronic stress and inflammation can become abuse appear to share the common mechanisms of sensitization of maladaptive and lead to neuropsychiatric disease such as depres- circuitry through increased HMGB1 and TLR signaling. sion. Indeed, the similarities between sickness behavior and Alcohol administration to mice and rats increases expression of depression have been noted (Maes et al., 2012). Models of HMGB1 and multiple TLR receptors in brain that persist for long depression include endotoxin treatments of rodents followed periods of abstinence. Furthermore, human post-mortem alcoholic beyond the 24 h “sickness behavior” time course (Dantzer et al., brains show increased expression of microglial markers, cytokines, 2008). The inflammation caused by excessive alcohol consump- TLR receptors and HMGB1, with the latter two being correlated tion may have similar maladaptive consequences. with lifetime alcohol consumption. Repeated alcohol, drug use and Studies have found similar mechanisms through which stress stress in rodents sensitize microglia toward hyperactivity, likely and alcohol contribute to inflammation (Fig. 2). Stress enhances through induction of immune signaling (see Sections 2 and 5). intestinal
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