Immune system to brain signaling: neuropsychopharmacological implications

Abstract

There has been an explosion in our knowledge of the pathways and mechanisms by which the immune system can influence the brain and behavior. In the context of inflammation, pro-inflammatory cytokines can access the central nervous system and interact with a cytokine network in the brain to influence virtually every aspect of brain function relevant to behavior including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits that regulate mood, motor activity, motivation, anxiety and alarm. Behavioral consequences of these effects of the immune system on the brain include depression, anxiety, fatigue, psychomotor slowing, anorexia, cognitive dysfunction and sleep impairment; symptoms that overlap with those which characterize neuropsychiatric disorders, especially depression. Pathways that appear to be especially important in immune system effects on the brain include the cytokine signaling molecules, p38 mitogen-activated protein kinase and nuclear factor kappa B; indoleamine 2,3 dioxygenase and its downstream metabolites, kynurenine, quinolinic acid and kynurenic acid; the neurotransmitters, serotonin, dopamine and glutamate; and neurocircuits involving the basal ganglia and anterior cingulate cortex. A series of vulnerability factors including aging and obesity as well as chronic stress also appears to interact with immune to brain signaling to exacerbate immunologic contributions to neuropsychiatric disease. The elucidation of the mechanisms by which the immune system influences behavior yields a host of targets for potential therapeutic development as well as informing strategies for the prevention of neuropsychiatric disease in at risk populations.

Figure 1. Temporal Evolution of the Neuropsychiatric Symptoms Induced by Chronic Interferon-alpha Therapy

Interferon (IFN)-alpha therapy induces two types of behavioral symptoms with differential time course and responsiveness to antidepressants. The neurovegetative symptoms (e.g., fatigue, anergia and psychomotor slowing) develop rapidly (as soon as week 1 [W1]) in almost every individuals exposed to cytokines and persist during the duration of IFN-alpha therapy. These symptoms are minimally responsive to antidepressant treatment. In contrast, the mood and cognitive symptoms (e.g., depressed mood, anxiety, irritability, memory and attentional disturbance) develop in vulnerable patients at later stages of IFN-alpha therapy (between weeks 8–12) and are highly responsive to antidepressant medication (Capuron et al., 2002a).

Figure 2. Communication Pathways from the Periphery to the Brain

Different pathways by which cytokine signals access the brain have been identified.

1. Humoral pathway: Pro-inflammatory cytokines released by activated monocytes and macrophages access the brain through leaky regions of the blood-brain barrier such as the choroid plexus and circumventricular organs (CVOs). Within the brain parenchyma, the activation of endothelial cells is responsible for the subsequent release of second messengers (e.g., prostaglandins [PGE2] and nitric oxide [NO]) that act on specific brain targets.

2. Neural pathway: Pro-inflammatory cytokines released by activated monocytes and macrophages stimulate primary afferent nerve fibers in the vagus nerve. Sensory afferents of the vagus nerve relay information to brain areas through activation of the nucleus of the tractus solitarius (NTS) and area postrema.

3. Cellular Pathway: A cellular pathway has been recently described by which pro-inflammatory cytokines, notably TNF-alpha, are able to stimulate microglia to produce monocyte chemoattractant protein-1 (MCP-1), which in turn is responsible for the recruitment of monocytes into the brain (D’ Mello et al., 2009).

Abbreviations: Interleukin-6: IL-6; interleukin-1β: IL-1β; tumor-necrosis factor: TNF

Figure 3. Pathways to Cytokine-Induced Pathology

Once cytokine signals reach the brain, they can interact with virtually every pathophysiologic domain relevant to mood regulation. These include effects on neurocircuits that regulate motor activity and motivation (basal ganglia) and mood, anxiety, arousal and alarm (anterior cingulate cortex); effects on growth factors such as brain derived neurotrophic factor, neurogenesis and ultimately synaptic plasticity; effects on the metabolism of monoamine neurotransmitters such as serotonin and dopamine as well as excitatory amino acid neurotransmitters such as glutamate; and effects on neuroendocrine function leading to glucocorticoid resistance and altered glucocorticoid secretion. Abbreviations: Interleukin-6: IL-6; interleukin-1β: IL-1β; tumor-necrosis factor: TNF

Figure 4. An Inflammatory Imbalance of T cell Subsets

Chronic inflammation may be maintained as the result of a preferential differentiation of T cell subsets toward a T helper (Th17) phenotype at the cost of T regulatory cell (T reg) development. Exposure to cytokines derived from dendritic cells and other immune cell types including the proinflammatory cytokines, IL-1β and IL-6, in conjunction with IL-23, increases the expression of the transcription factor, retinoid-related orphan receptor (ROR)c, which ultimately drives differentiation of the naïve T cell to the highly proinflammatory Th17 cell subset. In contrast, the anti-inflammatory cytokines TGF-beta and IL-10 promote the development of the counter-regulatory, anti-inflammatory T regulatory cell subset. Abbreviations: FoxP3: Forkhead box P3; Interleukin-6: IL-6; interleukin-1β: IL-1β; Interleukin-10: IL-10; transforming growth factor: TGF

Figure 5. Obesity-related Chronic Inflammation

In obesity, fat accumulation leads to the development of chronic low grade inflammation. This systemic inflammation originates primarily from the adipose tissue in which macrophages accumulate and secrete pro-inflammatory cytokines and monocyte chemoattractant protein-1 (MCP-1), which in turn increases macrophage infiltration. Adipocytes in obesity are also able to secrete inflammatory factors, including tumor necrosis factor (TNF)-alpha and adipokines and related hormones (e.g., increased secretion of leptin, resistin and visfatin and decreased secretion of adiponectin) which also contribute to non-resolving inflammation.