Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior

Abstract

The potential contribution of chronic inflammation to the development of neuropsychiatric disorders such as major depression has received increasing attention. Elevated biomarkers of inflammation, including inflammatory cytokines and acute-phase proteins, have been found in depressed patients, and administration of inflammatory stimuli has been associated with the development of depressive symptoms. Data also have demonstrated that inflammatory cytokines can interact with multiple pathways known to be involved in the development of depression, including monoamine metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits relevant to mood regulation. Further understanding of mechanisms by which cytokines alter behavior have revealed a host of pharmacologic targets that may be unique to the impact of inflammation on behavior and may be especially relevant to the treatment and prevention of depression in patients with evidence of increased inflammation. Such targets include the inflammatory signaling pathways cyclooxygenase, p38 mitogen-activated protein kinase, and nuclear factor-κB, as well as the metabolic enzyme, indoleamine-2,3-dioxygenase, which breaks down tryptophan into kynurenine. Other targets include the cytokines themselves in addition to chemokines, which attract inflammatory cells from the periphery to the brain. Psychosocial stress, diet, obesity, a leaky gut, and an imbalance between regulatory and pro-inflammatory T cells also contribute to inflammation and may serve as a focus for preventative strategies relevant to both the development of depression and its recurrence. Taken together, identification of mechanisms by which cytokines influence behavior may reveal a panoply of personalized treatment options that target the unique contributions of the immune system to depression.

Figure 1

Immune cell trafficking in CNS resilience and pathology. Immune cell trafficking to the brain can have important roles in mental health and illness, including (a) the delivery of anti-inflammatory molecules that can promote neuronal integrity and resilience, and (b) the communication of inflammatory signals, which may contribute to pathology. For example, (a) during stress, the production of glucocorticoids increases the expression of ICAM-1 by choroid plexus cells, which then attracts CD4+ T cells to the brain. Production of IL-4 by these T cells has been shown to shift the phenotype of meningeal myeloid cells (eg, macrophages) from an M1 (or proinflammatory) phenotype to an M2 (or anti-inflammatory) phenotype. In addition, IL-4, which enters the circulation or the CSF, can diffuse into brain parenchyma and induce glial elements, including astrocytes, to produce BDNF, which promotes neurogenesis and synaptic plasticity. By contrast, (b) peripherally elaborated TNF-α can lead to the activation of microglia, which in turn produce the chemokine, MCP-1. MCP-1 attracts monocytes to the brain where they enter the brain parenchyma as activated macrophages, capable of producing TNF-α as well as additional inflammatory mediators such as other inflammatory cytokines and reactive nitrogen and oxygen species.

Figure 2

IDO and the kynurenine pathway in inflammation-induced CNS pathology. Cytokine-induced activation of IDO in peripheral immune cells (eg, macrophages and dendritic cells) or cells in the brain (eg, microglia, astrocytes, and neurons) leads to the production of kynurenine, which is converted to KA by KAT-II in astrocytes or quinolinic acid by kynurenine-3-monooxygenase (KMO) and 3-hydroxy-anthranilic acid oxygenase (3-HAO) in microglia or infiltrating macrophages. Through blockade of the α7nAChR, KA can reduce glutamate release as well as the release of dopamine, both of which can contribute to cognitive dysfunction. By contrast, quinolinic acid through activation of the NMDA receptor can increase glutamate release as well as lead to lipid peroxidation, thus contributing to excitotoxicity, oxidative stress, and ultimately neurodegeneration.

Figure 3

Tetrahydrobiopterin: Target for inflammatory effects on neurotransmitter metabolism. Tetrahydrobiopterin (BH4) is a critical cofactor for the rate-limiting enzymes involved in the synthesis of the monoamine neurotransmitters, including (1) the synthesis of tyrosine (tyr) from phenylalanine (phe) by PAH; (2) the synthesis of -3,4-dihydroxyphenylalanine (-DOPA) from tyrosine (tyr) by tyrosine hydroxylase (TH) leading to the production of dopamine and norepinephrine; and (3) the synthesis of 5-hydoxy--tryptophan (5-HTP) from tryptophan (tryp), leading to the production of serotonin. In addition, BH4 is a cofactor for the enzyme NOS, which converts arginine (arg) to NO. During these enzymatic reactions, BH4 is degraded to BH2, which can be regenerated to BH4 through pathways supported by folic acid, L-methylfolate, and SAMe. BH4 is relatively unstable and in the context of inflammation and oxidative stress can undergo non-enzymatic oxidation leading to the irreversible degradation of BH4 to XPH².

Figure 4

Factors contributing to chronic, non-resolving inflammation and disease. Numerous environmental and biological factors can conspire to contribute to chronic inflammation, including stress, adiposity, dietary intake, the bacterial composition of the gut microbiota, and the relative balance of T-cell subpopulations, including proinflammatory Th-17 cells and anti-inflammatory T regs. Through both epidemiologic and mechanistic studies, chronic inflammation, in turn, is now recognized to be a common pathway to pathology, having a role in a diverse set of illnesses, including cardiovascular disease, diabetes, cancer and depression. Strategies targeting these contributors to chronic inflammation represent an important approach to the prevention and treatment of these diseases.