An inflammatory review of glucocorticoid actions in the CNS

Abstract

In recent years, the classic view that glucocorticoids, the adrenal steroids secreted during stress, are universally anti-inflammatory has been challenged at a variety of levels. It was first observed that under some circumstances, acute GC exposure could have pro-inflammatory effects on the peripheral immune response. More recently, chronic exposure to GCs has been found to have pro-inflammatory effects on the specialized immune response to injury in the central nervous system. Here we review the evidence that in some cases, glucocorticoids can increase pro-inflammatory cell migration, cytokine production, and even transcription factor activity in the brain. We consider how these unexpected effects of glucocorticoids can co-exist with their well-established anti-inflammatory properties, as well as the considerable clinical implications of these findings.

Introduction

Because life is frequently not easy, simple and complex organisms have developed methods to deal with challenging situations. In humans and other vertebrates, stressful circumstances elicit a wide variety of physiological changes that constitute the “stress-response.” This begins within seconds with the release of the catecholamines of the sympathetic nervous system (epinephrine and norepinephrine). In the ensuing minutes, the hypothalamic–pituitary–adrenal (HPA) axis is activated. CRF produced by the hypothalamus acts on the pituitary to activate the release of ACTH into circulation, resulting in the release of the adrenal steroid glucocorticoids (GCs). The role of GCs is largely to modulate and control the stress response over a longer timeframe in the minutes to hours following a stressor. This response is conducted largely on a genomic level and accordingly the actions of GCs are numerous and varied (Sapolsky et al., 2000).

The pioneering physiological investigations of Walter Cannon and Hans Selye in the early 20th century began to define precisely what is involved in the stress response. “Fight or flight,” as described by Cannon, reflects the actions of both catecholamines and GCs (although the latter were unknown until the work of Selye, some years later) to immediately increase cardiovascular output and blood flow to the brain and skeletal muscles. This is predominately mediated by catecholamines, although GCs potentiate their effects. Both hormones mobilize energy stores from adipose and hepatic cells, ensuring a supply of energy to exercising muscle. At the same time, GCs decrease less immediately essential activities such as feeding, digestion, growth, and reproduction. Of key relevance to this review, the ability of stress and GCs to inhibit the immune system was recognized soon after their discovery. The rationale for GCs diverting stored energy to exercising muscle is clear. It is less clear why it would be adaptive for stress to reduce the activity of the immune system, particularly because a stress response is often accompanied, or even caused by an immune challenge. There is little reproductive value to an injured animal that escapes a predator only to succumb to sepsis soon after.

Several theories were offered early on to help explain the supposed adaptive logic of suppressing immunity during stress (reviewed in (Munck et al., 1984)). The most pervasive of these was the explanation that the anti-inflammatory actions of GCs during stress were a means to conserve energy for a more critical need such as exercising muscle. The strongest blow to this hypothesis was evidence that GCs prevent inflammation via immune cell apoptosis, a type of programmed cell death that is a costly, pro-active enterprise requiring considerable amounts of protein synthesis and cellular remodeling. Moreover, these early theories could not satisfactorily circumvent the problem that dismantling the immune system in response to stress is often quite maladaptive.

In more recent years, the advent of improved assays that allowed for the detection of subtler changes in immune function with better time resolution radically changed the understanding of the effects of stress on the immune system. Specifically, it became clear that early in the stress response, before the stress-induced rise in GC levels can have its effects on target tissues, immune function is activated rather than suppressed (Herbert and Cohen, 1993). Munck and colleagues, in a highly influential theoretical paper, posited that the anti-inflammatory effect of elevated concentrations of GCs serves to mediate recovery, after the stressor has abated, from the immune-activating effects of the early phases of the stress response (Munck et al., 1984). Part of this reformulation involved the predication that failure of GCs to mediate this immune recovery would cause a predisposition towards developing autoimmune and inflammatory disorders. Subsequent work has supported this idea, showing that a number of autoimmune disorders, in both experimental animal models and humans, involve a failure of GC actions (Wick et al., 1993). It is these long-term potent anti-inflammatory effects of GCs that are used clinically to counter such autoimmune and inflammatory disorders.

The stimulatory effects of the early phases of stress on the immune response are in many cases due to the actions of catecholamines. However, GCs have also been found to be involved in this immune activation, raising the question of how GCs can both stimulate and suppress the immune response, albeit at different times. To reconcile these observations, Munck suggested that these opposing actions are concentration-dependent (Munck et al., 1984). Basal and low stress levels of GCs are required for the early increases in the immune response. This constitutes a common phenomenon in endocrinology, namely a “permissive” effect. In this case, low GC levels are needed to allow catecholamines to rapidly stimulate immunity with the onset of stress. Only at higher concentrations do GCs begin to exert suppressive effects to prevent autoimmune damage. This explanation fits well into an adaptive understanding of the immune system during the stress response where it needs to be mobilized initially, but must be kept under control in the long term.

More recently, GCs have been found to have pro-inflammatory effects in situations other than the early phase of the stress-response. In particular, the effects of chronic GCs on the immune response in the brain are surprisingly different from the classic picture of suppression in the periphery. Depending on the brain region, chronic exposure to GCs is often not anti-inflammatory and, in greatest contrast to dogma, can actually exacerbate various aspects of inflammation. This is in stark contrast to the effects of high concentrations of GCs in the periphery. The importance of these findings and their application cannot be sufficiently underscored, given the wide use of steroids in clinical neurology for their anti-inflammatory properties.

This review evaluates the evidence that GCs are not universally anti- inflammatory and the situations where they have pro-inflammatory actions. First, we briefly consider the wide range of anti-inflammatory effects of GCs on peripheral inflammation. We then review the more recent studies that suggest GCs enhance peripheral inflammation, particularly in the early phases of the stress response. Finally, we turn to the focus of this review, the injured CNS, where we consider recent evidence that chronic GCs can enhance some facets of inflammation in ways quite different from the cases of the pro-inflammatory effects of acute GCs in the periphery.