Bi-directional immune–brain communication: Implications for understanding stress, pain, and cognition

Abstract

The immune system and the central nervous system form a bi-directional communication network. The critical roles of pro-inflammatory cytokines in both the periphery and the nervous system are discussed. In the periphery, these cytokines initiate the processes that signal the brain that immune activation has occurred, and communicate this information over both neural and blood-borne routes. The arrival of these signals in the central nervous system induces a neural cascade that includes the de novo induction of pro-inflammatory cytokines. The functions of these cytokines in the nervous system are discussed, and it is argued that they play a key role in regulating the neural control of immune processes in the periphery. In addition, it is argued that these cytokines play a variety of other roles, and some implications of the cytokine network for understanding stress, behavior, sensory processing, mood, and cognition are described. The overall argument is that because brain-mediated host defense involves behavioral, sensory, mood, and cognitive alterations, immune activation, and immune products such as the cytokines can have a pervasive effect on these functions. Finally, these phenomena are placed in an evolutionary perspective.

Introduction

Non-specific immune defense begins rapidly following the entry of microbial products into the body, with conserved molecular patterns on infectious microorganisms (pathogen-associated molecular patterns, PAMPS) binding to specific recognition sites on cells such as neutrophils, dendritic cells, and macrophages (Medzhitov & Janeway, 1998). Lipopolysaccharide (LPS), a constituent of the cell wall of gram negative bacteria, and peptidoglycan and lipoteichoic acid from gram positive bacteria are examples, and bind to specific families of Toll-like receptors on the surface of cells of the non-specific immune system, thereby leading to rapid activation. These activated cells can engulf and destroy pathogenic agents and also release a variety of products, some of which act directly to kill microorganisms and/or slow their rate of replication. For example, reactive oxygen species can lyse pathogens, and nitric oxide can interfere with mitochondrial respiration, thereby slowing replication. Activated immune cells also synthesize and release pro-inflammatory cytokines. These proteins play a critical role in bringing additional immune cells to the site of infection or injury, and also initiate the peripheral acute phase response (Baumann & Gauldie, 1994). The liver shifts its activity and reduces its production of negative acute phase reactants such as albumin and carrier proteins, and produces increased quantities of positive acute phase reactants such as C-reactive protein and haptoglobin. In addition, there are alterations in plasma ions such as iron, copper, and zinc, all changes that promote survival during infection.

However, host defense against infection and recovery from tissue injury also involves elements that are orchestrated by the central nervous system. This means that there must be pathways from the immune system to the brain. This crucial insight has several sources. The oldest comes from the study of fever. Fever is a highly conserved and adaptive response to infection (Kluger, Kozak, Conn, Leon, & Soszynski, 1996). It is adaptive because many microorganisms replicate best at the normal core body temperature of the host, white blood cells divide more rapidly at elevated temperatures, and a number of enzymatic processes that are involved in the killing of microorganisms proceed more rapidly at elevated temperatures. By the 1960s it had become clear that fever is not just hyperthermia created by the action of pathogens in the periphery, but rather reflects a regulated increase in core body temperature that occurs because the set point for body temperature is increased in hypothalamic neurons. It also became clear at this time that fever does not result from the direct action of microorganisms, but that instead pathogens lead phagocytic cells such as macrophages to release substances that are responsible for producing fever. These were called endogenous pyrogens.

The pioneering work of Hugo Besedovsky and his colleagues is a second line of evidence. This thread goes back to at least 1977 when Besedovsky, Sorkin, Felix, and Harris demonstrated that neuronal firing rates in the ventromedial nucleus of the hypothalamus increase at the peak of the primary antibody response. This and related types of work led both Besedovksy and Edwin Blalock to propose that the immune system functions as a diffuse sense organ informing the brain about events related to infection and injury. Indeed, Blalock published a paper in 1984 titled “The Immune System as a Sensory Organ.”

The final source stems from a particular paper published in 1988 by Benjamin L. Hart entitled “Biological Basis of the Behavior of Sick Animals.” In this seminal paper Hart argued that the behavior of sick animals, in which he included fever, anorexia, reduced activity, sleep, and depression, is not a maladaptive effect of illness, but rather an evolved and organized strategy to help combat infection. Obviously, changes in behavior are a product of changes in neural activity, so the brain must be involved in orchestrating responses to infection and injury. Hart also argued that fever is likely the key to understanding the sickness pattern. Although adaptive, Hart noted that fever is very energy intensive, requiring an extra 10–13% or so of energy for each degree rise in core body temperature. Hart argued that the sickness pattern could be understood as a coordinated effort to reduce the energetic cost of behavior so that available energy stores could be used to raise core body temperature. Although not noted by Hart, immune activation also leads to a classic stress response—hypothalamo–pituitary–adrenal (HPA) and sympathetic nervous system (SNS) activation. The endpoints of these systems, glucocorticoids and catecholamines, function to create energy by converting glycogen to glucose breaking down protein into amino acids, and so forth. HPA and SNS activity are, of course, controlled by the brain. Thus, the sickness pattern can be considered to include an effort, coordinated by the brain, to conserve and create energy for fever. Finally, it should be noted that the significance of the Hart paper (and a subsequent paper) was not widely recognized, and that it was the work of Robert Dantzer and his colleagues (e.g., Kent, Bluthe, Kelley, & Dantzer, 1992) that made the function of “sickness behavior” and the role of the brain in host defense clear.

The brain-mediated sickness responses discussed above (e.g., sleep) are direct products of neural activity in the sense that their occurrence does not involve peripheral organs or immune cells. However, the brain is also important in regulating the action of peripheral organs and immune cells during host defense (see below). Thus, there must also be pathways from the brain to the immune system, and these are well known. Terminals of the SNS innervate immune organs (Felten et al., 1985) and cells of the immune system express receptors for catecholamines (Sanders, Kosprowicz, Kohm, & Swanson, 2001) as well as HPA axis and other hormones (Miller et al., 1998).

Thus, the immune system and the central nervous system form a bi-directional communication network. The purposes of the present paper are to (a) discuss the critical role of pro-inflammatory cytokines in both the periphery and the central nervous system in this bi-directional network, and (b) examine some implications of this network and cytokines for understanding stress, behavior, sensory processing, mood, and cognition. The overall argument will be that because brain-mediated host defense involves behavioral, sensory, mood, and cognitive alterations, immune activation, and immune products such as the cytokines can have a more pervasive effect on these functions than has generally been realized and can aid in the understanding of a number of poorly understood aspects of these processes.