Neuroimmune pathways in alcohol consumption: evidence from behavioral and genetic studies in rodents and humans

Abstract

Immune or brain proinflammatory signaling has been linked to some of the behavioral effects of alcohol. Immune signaling appears to regulate voluntary ethanol intake in rodent models, and ethanol intake activates the immune system in multiple models. This bidirectional link raises the possibility that consumption increases immune signaling, which in turn further increases consumption in a feed-forward cycle. Data from animal and human studies provide overlapping support for the involvement of immune-related genes and proteins in alcohol action, and combining animal and human data is a promising approach to systematically evaluate and nominate relevant pathways. Based on rodent models, neuroimmune pathways may represent unexplored, nontraditional targets for medication development to reduce alcohol consumption and prevent relapse. Peroxisome proliferator-activated receptor agonists are one class of anti-inflammatory medications that demonstrate antiaddictive properties for alcohol and other drugs of abuse. Expression of immune-related genes is altered in animals and humans following chronic alcohol exposure, and the regulatory influences of specific mRNAs, microRNAs, and activated cell types are areas of intense study. Ultimately, the use of multiple datasets combined with behavioral validation will be needed to link specific neuroimmune pathways to addiction vulnerability.

Keywords: Dependence; Ethanol; Gene expression; Human alcoholics; Knock-out mice; LPS; PPAR; Preference; TLR4; Two-bottle choice; mRNA; microRNA.

Figure 2.1

TLR4 signaling cascade. TLRs signal as dimers and heterodimers that recruit adaptor proteins such as CD14 and MD2. Depending on the adaptors recruited by the activated TLR, different pathways are triggered, all of which culminate in activation of the proinflammatory transcription factors. One pathway involves MyD88 and TIRAP and activates NF-κB via IκB kinase and also activates AP-1. Another pathway involving NADPH oxidase activates NF-κB via ROS. TRIF and TRAM signaling proteins (via MyD88-independent pathway) also initiate signal cascades, culminating in activation of NF-κB and other proinflammatory transcription factors. RAGE is another transmembrane receptor operating in innate immune cells that is known to respond to HMGB1, and this pathway also induces proinflammatory gene transcription via NF-κB activation. The release of cytokines such as TNF-α, HMGB1, IL-1β, chemokines, proteases, and ROS activate adjacent cells. These cytokines affect the brain and are thought to contribute to the etiology, progression, and persistence of alcohol addiction. Bold red font (bold grey in the print version) indicates a gene that has been manipulated and shown to affect ethanol-related behavior. NF-κB, nuclear factor-κ-light-chain-enhancer of activated B cells; MyD88, myeloid differentiation primary response gene 88; AP-1, activated protein-1; TIRAP, toll-interleukin-1 receptor (TIR) domain containing adaptor protein; ROS, reactive oxygen species; TRIF, TIR-domain-containing adaptor-inducing IFNβ; IRF, interferon regulatory factor; TRAM, TRIF-related adaptor molecule; RAGE, receptor for advanced glycation end products; TNF-α, tumor necrosis factor-α; IL-1 β, interleukin-1β; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein-1.

Figure 2.2

Negative regulation of transcription factors by PPARs. The inflammatory and immunomodulatory properties of peroxisome proliferator-activated receptors (PPARs) do not arise primarily through their transcription-factor transactivation abilities, but rather through their ability to antagonize several important signaling cascades. Although different transrepression mechanisms exist, three are mediated by PPARs in cells of the immune system. (A) The first mechanism is the ability of PPARs to compete for limiting amounts of coactivator proteins in a cell, such as cAMP response element binding (CREB)-binding protein (CBP) and steroid receptor coactivator 1 (SRC1), making these coactivators unavailable to other transcription factors (TFs). (B) The second mechanism is known as “cross coupling” or “mutual receptor antagonism” and is facilitated by the ability of PPARs to associate physically with various transcription factors, preventing the transcription factor from binding to its response element and thereby inhibiting its ability to induce gene transcription. (C) Another transrepression mechanism relies on the ability of the PPAR to inhibit activation of a mitogen-activated protein kinase (MAPK). This inhibits the MAPK from phosphorylating and activating downstream transcription factors. RXR, 9-cis-retinoic acid receptor. Figure and legend are from Daynes and Jones (2002).

Figure 2.3

Hypothetical model for neuroimmune-related actions of microRNAs in brain of human alcoholics (e.g., in microglia). Bacterial lipopolysaccharides (LPSs) from commensal bacteria may leak into the bloodstream resulting from gut leakiness induced by alcohol consumption. Activation of NF-κB induces the transcription of a variety of proinflammatory and miRNA genes. Newly synthesized proinflammatory factors induce a systemic neuroinflammatory response and a positive-feedback loop in the same activated cell. Subsequent generation of proinflammatory factors results from expression of alternative cytokine receptors in the activated cell, which signal back to the nucleus to induce additional proinflammatory factors (e.g., interferons) and miRNA genes. To avoid overamplification of these signals and excessive inflammation, specific miRNAs (e.g., members of the miR-146, miR-152, and let-7 families) are consequently upregulated, suppressing TLR4/CXCR4 signaling through inhibition of various transducers, such as IL1 receptor-associated kinases (IRAKs), TNF receptor-associated factor 6 (TRAF6), and TLR4/CXCR4 itself. As a compensatory reaction, miRNAs (e.g., miR-203) may also be upregulated to maintain the immune-activated state of the specific cell subtype while promoting a benign, contained inflammatory response. microRNAs that target epige-netic factors are also activated to control and/or fine tune the ongoing remodeling of the cellular epigenome, allowing for long-term homeostatic and cellular adaptations. Figure and legend are from Nunez and Mayfield (2012).