Immune regulation by glucocorticoids

Abstract

Endogenous glucocorticoids are crucial to various physiological processes, including metabolism, development and inflammation. Since 1948, synthetic glucocorticoids have been used to treat various immune-related disorders. The mechanisms that underlie the immunosuppressive properties of these hormones have been intensely scrutinized, and it is widely appreciated that glucocorticoids have pleiotropic effects on the immune system. However, a clear picture of the cellular and molecular basis of glucocorticoid action has remained elusive. In this Review, we distil several decades of intense (and often conflicting) research that defines the interface between the endocrine stress response and the immune system.

Figure 1 |. Regulation of glucocorticoid production by the hypothalamic–pituitary–adrenal axis.

The hypothalamus responds to circadian cues, stress (real or perceived) and inflammatory cytokines by producing corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). CRH and AVP act on the anterior pituitary gland to induce the synthesis and secretion of adrenocorticotropin hormone (ACTH). ACTH enters the circulation and binds receptors on adrenocortical cells to stimulate steroidogenesis (indicated by the dark blue dashed arrows). Activation of Toll-like receptor 2 (TLR2) and TLR4 on adrenocortical cells also triggers steroidogenesis. During steroidogenesis, cholesterol undergoes a series of enzymatic changes that result in the production of glucocorticoids. Cortisol and corticosterone are the primary glucocorticoids in humans and rodents, respectively. Glucocorticoids enter the circulation for distribution throughout the body. Glucocorticoids negatively regulate the hypothalamic–pituitary–adrenal (HPA) axis by feeding back on the hypothalamus and pituitary gland, and by decreasing the expression of pro-inflammatory cytokines. IL, interleukin; TNF, tumour necrosis factor.

Figure 2 |. Mechanisms of glucocorticoid activity.

In the extracellular space, most endogenous glucocorticoids (GCs) are inactive owing to binding with corticosteroid-binding globulin (CBG). Unbound cortisol is lipid soluble and diffuses through cell membranes. Cortisol that enters the cytoplasm can be converted into inactive cortisone through enzymatic modification by 11β-hydroxysteroid dehydrogenase 2 (11βHSD2), whereas 11βHSD1 favours the reverse reaction. Cortisol intercalation into plasma membranes can exert non-genomic effects. Cytoplasmic cortisol binds the GC receptor (GR) as part of a chaperone complex. The ligand-bound GR translocates to the nucleus to exert genomic effects, or has non-genomic effects in the cytoplasm and mitochondria. Within the nucleus, the liganded GR alters gene expression through three basic mechanisms: direct binding to GC response elements (+GREs) or negative GREs (nGREs); protein–protein interactions with other transcription factors (TFs) that affect their transcriptional activity; and composite binding to DNA and protein substrates. Notably, positive and negative gene regulation is possible for each of these mechanisms. RE, response element; TM, transcriptional machinery.

Figure 3 |. Effects of glucocorticoids on inflammation.

a | In healthy tissue, tissue-resident macrophages, fibroblasts and stromal cells express pattern recognition receptors (PRRs) and scavenger receptors (SRs). Mast cells bind soluble IgE via Fcε receptors (FcεRs). b | During the alarm phase of inflammation, pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) trigger PRR signalling, which induces the production of inflammatory mediators, including cytokines, prostaglandin E₂ (PGE₂) and leukotriene B4 (LTB4). Antigens bind FcεR-bound IgE on mast cells to induce histamine release. Glucocorticoids (GCs) dampen signalling through PRRs, FcεRs and cytokine receptors. c | During the mobilization phase of inflammation, inflammatory mediators induce the display of adhesion molecules — including E-selectin, chemokines and integrins — on the vascular endothelium to recruit leukocytes, especially polymorphonuclear leukocytes (PMNs), into the tissue. Extravasating leukocytes follow chemokine gradients towards inflammatory sites. GCs inhibit the expression of E-selectin, chemokines and integrins to reduce leukocyte recruitment. d | During the resolution phase of inflammation, GCs promote the differentiation of alternatively activated ‘M2c’ macrophages, which clear apoptotic PMNs and secrete anti-inflammatory factors. e | The resolution of inflammation triggers wound healing, which is characterized by re-epithelialization, collagen deposition and angiogenesis. As GCs inhibit these processes, optimal wound healing probably depends on reduced glucocorticoid production. IL, interleukin; TGFβ, transforming growth factor-β; TNF, tumour necrosis factor.

Figure 4 |. Glucocorticoids inhibit signalling through Toll-like receptors.

Glucocorticoid receptors (GRs) regulate various points in the Toll-like receptor (TLR) signalling cascade, and many of these steps are shared with other immune receptors. The activated GR enhances the transcription of genes encoding TLR signalling inhibitors, including interleukin1 receptor-associated kinase 3 (IRAK3), dual-specificity protein phosphatase 1 (DUSP1), inhibitor of nuclear factor-κB (IκB) and glucocorticoid-induced leucine zipper (GILZ). The liganded GR also represses the activity of pro-inflammatory transcription factors — including activator protein 1 (AP-1), nuclear factor-κB (NF-κB) and interferon-regulatory factor 3 (IRF3) — through protein–protein interactions. IKKε, IκB kinase-ε; JNK, JUN N-terminal kinase; MKK, mitogen-activated protein kinase kinase (also known as MAP2K); MYD88, myeloid differentiation primary response protein 88; TAK1, transforming growth factor-β-activated kinase 1 (also known as MAP3K7); TBK1, TANK-binding kinase 1; TM, transcriptional machinery; TRIF, TIR domain-containing adapter protein inducing IFNβ (also known as TICAM1).

Figure 5 |. Glucocorticoids modulate T cell activity.

a | Glucocorticoids (GCs) suppress CD4⁺ T cell activation indirectly by modulating dendritic cell (DC) function (antigen presentation, co-stimulation and cytokine production) and directly by regulating T cell receptor (TCR) signalling. b | GCs influence the polarization of T helper (T_H) cells, favouring the differentiation of T_H2 cells and regulatory T (T_reg) cells over that of T_H1 cells and T_H17 cells. The effects of GCs on the differentiation of T_H9 cells and T follicular helper (T_FH) cells require further investigation. AP-1, activator protein 1; GR, GC receptor; IL, interleukin; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor-κB; TNF, tumour necrosis factor.

Figure 6 |. Glucocorticoid-induced sensitization of innate immunity.

a | Genome-wide expression studies indicate that glucocorticoids (GCs) upregulate the expression of genes that are involved in the detection of pathogens and tissue trauma, including pattern recognition receptors (PRRs), cytokine receptors and complement factors, while inhibiting the expression of pro-inflammatory cytokines and chemokines. These studies have also revealed that genes involved in adaptive immunity are inhibited by GC exposure. b | A hypothetical timeline for immune responses occurring in the presence (red line) or absence (blue line) of GCs is shown. We propose that GCs regulate the immune system in a biphasic manner, such that low doses promote the expression of innate immune genes and rapid responses to insults, but stress and/or pharmacological concentrations suppress signalling through immune receptors. According to this hypothesis, GC-sufficient animals (red line) mount rapid immune responses to pathogens and tissue injury, but these responses are of controlled duration. In GC-insufficient animals (blue line), however, subnormal expression of PRRs and cytokine receptors results in a slower immune response. Furthermore, in the absence of GC-mediated suppression of immune receptor signalling, the duration of the immune response is prolonged. GR, GC receptor.