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.

Introduction

Reciprocal interactions between the immune system and the brain have attracted considerable attention regarding the role of the immune system in neuropsychiatric diseases especially major depression. During the last several decades, research in the field referred to as “Psychoneuroimmunology” has demonstrated an intricate network of bi-directional relationships between the immune system and the brain. Alterations in immune function have been found in depressed patients with major depression and include early reports of immune suppression (e.g., reduced natural killer cell activity and reduced lymphocyte proliferation) followed by evidence of increased inflammatory activity (e.g., increased circulating levels of inflammatory markers) (Kronfol et al., 1983, Irwin and Gillin, 1987, Maes et al., 1993, Anisman et al., 1999, Zorrilla et al., 2001). Much of the recent interest in the role of the immune system in depression has focused on increased inflammation associated with depression. Pro-inflammatory cytokines, including interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-alpha, are released by activated immune cells during the host response to pathogen invasion as well as in the context of tissue injury and psychosocial stress. These soluble factors appear to represent primary mediators of the communication between the immune system and the brain, and not only help orchestrate cellular responses to immune challenge, but also coordinate the behavioral changes that are necessary for recovery. During the course of immune challenge, the release of pro-inflammatory cytokines is usually transient and regulated by anti-inflammatory mechanisms. Consequently, the behavioral effects triggered by the activation of the inflammatory response develop as an adaptative, temporary and controlled reaction of the central nervous system (CNS) to immune signals. Nevertheless, when immune challenge becomes chronic and/or unregulated, as is observed in patients receiving chronic cytokine treatments or those exposed to chronic medical illness and/or stress, the behavioral effects of cytokines and the resultant inflammatory response may contribute to the development of clinically relevant behavioral symptoms and neuropsychiatric diseases, including major depression. These immune-based behavioral disorders, as well as the pathophysiological mechanisms involved will be discussed in this review along with relevant treatment implications.