Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications

Abstract

Mounting evidence indicates that inflammatory cytokines contribute to the development of depression in both medically ill and medically healthy individuals. Cytokines are important for development and normal brain function, and have the ability to influence neurocircuitry and neurotransmitter systems to produce behavioral alterations. Acutely, inflammatory cytokine administration or activation of the innate immune system produces adaptive behavioral responses that promote conservation of energy to combat infection or recovery from injury. However, chronic exposure to elevated inflammatory cytokines and persistent alterations in neurotransmitter systems can lead to neuropsychiatric disorders and depression. Mechanisms of cytokine behavioral effects involve activation of inflammatory signaling pathways in the brain that results in changes in monoamine, glutamate, and neuropeptide systems, and decreases in growth factors, such as brain-derived neurotrophic factor. Furthermore, inflammatory cytokines may serve as mediators of both environmental (e.g. childhood trauma, obesity, stress, and poor sleep) and genetic (functional gene polymorphisms) factors that contribute to depression's development. This review explores the idea that specific gene polymorphisms and neurotransmitter systems can confer protection from or vulnerability to specific symptom dimensions of cytokine-related depression. Additionally, potential therapeutic strategies that target inflammatory cytokine signaling or the consequences of cytokines on neurotransmitter systems in the brain to prevent or reverse cytokine effects on behavior are discussed.

Figure 1. Potential mechanisms of inflammatory cytokine effects on brain monoamine, glutamate, and BDNF neurotransmitter systems

Peripheral cytokines can access the central nervous system and increases production of local inflammatory mediators such as cyclooxegenase-2 (COX-2), prostaglandin E2 (PGE2), nitric oxide (NO), cytokines, and chemokines by endothelial cells, perivascular macrophages, and microglia. Production of monocyte chemotactic protein-1 (MCP-1) recruits peripheral immune cells into the brain that produce even more cytokines and inflammatory mediators. Inflammatory cytokines are associated with increased oxidative stress and generation of reactive oxygen and reactive nitrogen species (ROS and RNS). Increased ROS and RNS contribute to oxidation of tetrahydrobiopterin (BH4), a cofactor required for the synthesis of monoamines. Furthermore, evidence exists indicating that inflammatory cytokines and their signal transduction pathways, such as p38 mitogen-activated protein kinases (MAPK), may decrease expression or function of the vesicular monoamine transporter 2 (VMAT2) and/or increase expression or function of serotonin and dopamine transporters (5-HTT/DAT). Cytokines can also decrease brain-derived neurotrophic factor (BDNF) and interfere with TrkB receptor signaling, which may adversely influence neurogenesis and neuroplasticity. Finally, inflammatory cytokines can affect the glutamate (Glu) system by activation of the enzyme, indoleamine-2,3-dioxygenase (IDO), that catabolizes tryptophan, the primary amino-acid precursor of 5-HT, into kynurenine. Kynurenine is further broken down in the CNS into the neuroactive metabolites kynurenic acid and quinolinic acid (QUIN). Although not pictured, kynurenic acid can antagonize Glu receptors and decrease Glu release leading to decreased Glu neurotransmission. QUIN can directly activate the n-methyl-d-aspartate receptor (NMDAR), increase Glu release, and inhibit Glu uptake by astrocytes via the excitatory amino acid transporter (EAAT), thus allowing increased access of Glu to extrasynaptic NMDARs and contributing to excitotoxicity. 3-HAO, 3-hydroxyanthranilic acid oxygenase; 5-HT, serotonin; 5-HTT, serotonin transporter; AMPAR, 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid receptor; BH4, tetrahydrobiopterin; BDNF, brain-derived neurotrophic factor; COX-2, cyclooxygenase-2; DAT, dopamine transporter; glu, glutamate; EAAT, excitatory amino acid transporter; IDO, indoleamine 2,3 dioxygenase; IFN, interferon; iNOS, inducible nitric oxide synthase; IL, Interleukin; KAT II, kynurenine aminotransferase II; KMO, kynurenine 3-monooxygenase; MAPK, mitogen-activated protein kinases; MCP-1, monocyte chemotactic protein-1; NMDAR, N-Methyl-D-aspartic acid receptor; NF-kB, nuclear factor-kappa B; PGE2, prostaglandin E2; QUIN, quinolinic acid; RNS, reactive nitrogen species; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; TH, tyrosine hydroxylase; TNF, tumor necrosis factor; TrkB, tyrosine kinase receptor B; VMAT2, vesicular monoamine transporter 2