The HPA - Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain

Abstract

In response to physiological and psychogenic stressors, the hypothalamic-pituitary-adrenal (HPA) axis orchestrates the systemic release of glucocorticoids (GCs). By virtue of nearly ubiquitous expression of the GC receptor and the multifaceted metabolic, cardiovascular, cognitive, and immunologic functions of GCs, this system plays an essential role in the response to stress and restoration of an homeostatic state. GCs act on almost all types of immune cells and were long recognized to perform salient immunosuppressive and anti-inflammatory functions through various genomic and non-genomic mechanisms. These renowned effects of the steroid hormone have been exploited in the clinic for the past 70 years and synthetic GC derivatives are commonly used for the therapy of various allergic, autoimmune, inflammatory, and hematological disorders. The role of the HPA axis and GCs in restraining immune responses across the organism is however still debated in light of accumulating evidence suggesting that GCs can also have both permissive and stimulatory effects on the immune system under specific conditions. Such paradoxical actions of GCs are particularly evident in the brain, where substantial data support either a beneficial or detrimental role of the steroid hormone. In this review, we examine the roles of GCs on the innate immune system with a particular focus on the CNS compartment. We also dissect the numerous molecular mechanisms through which GCs exert their effects and discuss the various parameters influencing the paradoxical immunomodulatory functions of GCs in the brain.

Keywords: HPA axis; glucocorticoid receptor; glucocorticoids; inflammation; microglia; stress.

Figure 1

Activation cascade of the hypothalamic–pituitary–adrenal (HPA) axis by systemic immune stimuli. Integrated brain circuits trigger the parvocellular neurons of the PVN to release infundibular CRH, which stimulates the release of ACTH from corticotroph cells of the pituitary. ACTH reaches the bloodstream and finally induces the systemic release of GCs by the adrenals. PGE₂ may activate or inhibit neurons through the EP₄ and EP₃ receptors, respectively. ACTH, adrenocorticotrophic hormone; CRH, corticotrophin releasing factor; EP_1–4, PGE₂ receptor subtypes; GABA, γ-aminobutyric acid (inhibitory); NTS, nucleus tractus solitarius (A2/C2 neurons); PGE₂, prostaglandin of E2 type; PVN, paraventricular nucleus of the hypothalamus; VLM, ventrolateral medulla (A1/C1 neurons).

Figure 2

Genomic and non-genomic mechanisms through which GCs regulate gene transcription. Free circulating GCs easily diffuse through membranes such as the blood–brain barrier (BBB) and thus target both peripheral and CNS cells. The bioavailability of endogenous and exogenous GCs in the CNS is however limited at the organ level by efflux pumps expressed at the BBB and at the cellular level by enzymatic metabolism (11β-HSD enzymes). The unliganded GC receptor (GR) is sequestered in the cytoplasm by multiple chaperones. Ligation of the GR by a GC molecule (1:1 ratio) alters its conformation and results in the dissociation of the chaperones. The activated GR then translocates to the nucleus and dynamically modulate gene transcription through various mechanisms. Liganded GRs bind to four main types of GR-response elements (GREs). Activated GRs physically interact with DNA on simple (+GRE), negative (nGRE), and composite GREs (cGRE). The activated GR can also be recruited to other DNA-binding sequences (DBS) via protein–protein interactions (tGRE). Transactivation or transrepression activity of the GR is partly dictated by the type of GRE and its binding partners. Alternatively, GRs also regulate transcription through steric hindrance on DNA sites overlapping with GREs, by sequestering transcription factors from DNA and by competing for co-activators binding. Furthermore, liganded GRs may occupy other response elements by binding to overlapping GREs, sequester transcription factors from DNA and compete for co-activators.