Neuroinflammatory Processes in Drug Addiction

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), and the U54 collaborative partnership among NCCU, and UNC (AA019767), and K08-AA024829.

Innate Immune Signaling in the Brain

Immune Cells of the Brain

Historically the brain has been considered an “immune privileged” organ, meaning it is protected from immune activation that occurs in the periphery. Currently, this is largely considered true; however, the brain has its own immune defenses. The resident immune defenses in the brain are known to be composed of innate immune responses. This allows for recognition and elimination of viral, bacterial, and fungal pathogens. Historically, immune function in the brain has primarily been considered the role of glial—microglia and astrocytes. Microglia are the resident macrophages of the brain and derive from mesodermal tissue-specific monocytes. Microglia transition from a resting state to various stages of activation in response to infections, stressors, and drugs of abuse such as alcohol and cocaine. ^a

a References .

Stages of microglial activation have been traditionally classified as M1 (proinflammatory) and M2 (antiinflammatory). M1 activation is associated with the release of canonical proinflammatory cytokines such as tumor necrosis factor α (TNFα), interleukin 1β (IL-1β), and IL-6, as well as generation of reactive oxygen species (ROS) through increased inducible nitric oxide synthase (iNOS) and nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase expression. The M2 state is associated with the release of canonical antiinflammatory cytokines such as IL-10 and IL-4. Microglia also regulate physiological processes in the healthy brain, such as synaptic pruning, debris clearance, immune surveillance/defense, and neurogenesis. Astrocytes are another important cell type in the neuroimmune system. Astrocytes express immune receptors and cytokines in response to immune activation. Astrocytes undergo an activation known as reactive gliosis to help limit tissue damage in different contexts. Some suggest that astrocytes adopt proinflammatory and antiinflammatory states, similar to microglia. Astrocytes are also involved in numerous physiological processes, such as maintenance of fluid homeostasis, metabolic support of neurons, and modulation of synaptic transmission through uptake of glutamate. Both alcohol and cocaine also cause astrocyte activation. It is important to note that both microglia and astrocytes regulate synaptic plasticity. Thus their activation by drugs of abuse might result in synaptic changes and neuronal firing. Of interest, neurons have also been proposed to play a role in innate immune responses through modulation of glia and the induction of cytokines. In addition, a variety of cytokine receptors, such as those for, suggesting that neurons respond to cytokines. Indeed, IL-1β, monocyte chemoattractant protein-1 (MCP-1) and other immune-signaling molecules alter neuronal firing and modulates γ-aminobutyric acid (GABA) transmission. These studies indicate that in the brain, cytokines and other immune-signaling molecules modify synapses and neurocircuits similar to neurotransmitters.

Pattern Recognition Receptors and Their Ligands

The innate immune system functions to recognize foreign pathogens for their elimination. These pathogenic elements are detected by pattern recognition receptors (PRRs). These receptors recognize specific molecular signatures associated with bacteria and viruses, termed pathogen-associated molecular patterns (PAMPs). PRRs are promiscuous receptors that have also been found to recognize endogenous molecules associated with cell stress or trauma, known as damage-associated molecular patterns (DAMPs). This is considered “sterile” inflammation, when innate immune activation occurs without the presence of a foreign pathogen. The release of DAMPs has been implicated in the pathologies of numerous peripheral immunological diseases. DAMP release also occurs in the brain, which is normally a sterile environment. PRRs play critical roles in addiction pathology. To date, five classes of PRRs have been identified including: Toll-like receptors (TLRs), C-type lectin receptors, nucleotide binding domain receptors (leucine-rich repeat containing or nucleotide-binding oligomerization domain [NOD]-like receptors), RIG-I-like receptors, and absent in melanoma 2 (AIM2)-like receptors . TLRs are the most studied PRRs, and have been implicated in both cocaine and alcohol addiction. To date, 10 TLRs have been identified in humans and 12 in mice. TLR ligands include a variety of molecules from bacterial endotoxin to mammalian high-mobility group box 1 (HMGB1) and heat shock proteins ( Table 20.1 ). TLRs are characterized by an N-terminal extracellular leucine-rich repeat sequence and an intracellular Toll/IL-1 receptor/resistance motif (TIR). TLR signaling operates through key adapter proteins that initiate the signaling cascade upon ligand recognition. All TLRs, except for TLR3, utilize the MyD88 adapter protein complex. TIRAP/MyD88 complex formation causes activation of the IL-1 receptor–associated kinases (IRAKs) and the TNF receptor–associated factor 6 (TRAF6) leading to IκB and MAPK activation. IκB and MAPK activation result in activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activated protein-1 (AP-1) transcription factors, respectively. These transcription factors regulate the expression of proinflammatory cytokines that propagate and magnify the immune response. Because TLRs share common intracellular signaling with several cytokines, subsequent cytokine release leads to an amplification of immune responses. Activation of these transcription factors is involved in addiction (detailed below). TLR signaling was initially described in peripheral immune cells. Thus the precise signaling pathways for the TLRs in each brain cell type have yet to be delineated. Both microglia and astrocytes appear to show canonical TLR4 signaling in response to ethanol resulting in NF-κB activation. However, responses in neurons are poorly understood. There is debate on whether neurons are capable of activating NF-κB. Some suggest that neurons do,not while others find that NF-κB activation in glutamatergic and cultured neurons regulates plasticity, learning, and memory. Furthermore, activated NF-κB subunit colocalizes with dorsal horn spinal neurons and different neuronal cell lines exhibit NF-κB-dependent regulation of μ-opioid receptor expression.

Table 20.1

Selected Toll-like Receptors (TLRs) implicated in Addiction and Neurological Diseases

TLR	Foreign Immunogen	Endogenous TLR Ligand	Neuropsychiatric Disease
2	Bacterial di- and tri-acylated polypeptides Gram (+) lipoglyans	α-Synuclein	Alcoholism Parkinson disease
3	dsRNA	Stathmin, dsRNA	Alzheimer disease Multiple sclerosis
4	Bacterial endotoxin Peptidoglycans	HMGB1 HSPs 60, 70/72	Alcoholism Cocaine abuse Stroke, traumatic brain injury Chronic pain
7	ssRNA	Let-7, miR-21	Alcoholism Alzheimer disease Chronic pain

HMGB1. High-mobility group box.

A key feature of TLR signaling is the induction of proinflammatory DAMP release. These DAMPs can subsequently further TLR activation by binding to their respective receptors. Because the brain is sterile, TLR activation in the brain in response to drugs of abuse likely involves DAMP-mediated signaling. One such DAMP that has been found to play a role in alcohol addiction in particular is the protein high-mobility group box 1 (or HMGB1), a nuclear chromatin binding protein that can be released during cellular stress, activation, or damage. Upon its release, HMGB1 acts as an immune mediator via TLR4 or RAGE receptors. HMGB1 has been implicated in alcohol addiction pathology and might be involved in other drugs of abuse (detailed further later in this chapter). HMGB1 is also released prior to hyperexcitable states, such as seizures, and modulates glutamatergic signaling. Neuroimmune activation and neuronal signaling could be interconnected by DAMP release. Several cytokines have been found to regulate normal brain function and could be dysregulated by drugs of abuse. Thus DAMP and cytokine paracrine and autocrine signaling across glia through kinase cascades may represent brain plasticity mechanisms that could contribute to the development of addiction

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