More Than Suppression: Glucocorticoid Action on Monocytes and Macrophages

Abstract

Uncontrolled inflammation is a leading cause of many clinically relevant diseases. Current therapeutic strategies focus mainly on immunosuppression rather than on the mechanisms of inflammatory resolution. Glucocorticoids (GCs) are still the most widely used anti-inflammatory drugs. GCs affect most immune cells but there is growing evidence for cell type specific mechanisms. Different subtypes of monocytes and macrophages play a pivotal role both in generation as well as resolution of inflammation. Activation of these cells by microbial products or endogenous danger signals results in production of pro-inflammatory mediators and initiation of an inflammatory response. GCs efficiently inhibit these processes by down-regulating pro-inflammatory mediators from macrophages and monocytes. On the other hand, GCs act on "naïve" monocytes and macrophages and induce anti-inflammatory mediators and differentiation of anti-inflammatory phenotypes. GC-induced anti-inflammatory monocytes have an increased ability to migrate toward inflammatory stimuli. They remove endo- and exogenous danger signals by an increased phagocytic capacity, produce anti-inflammatory mediators and limit T-cell activation. Thus, GCs limit amplification of inflammation by repressing pro-inflammatory macrophage activation and additionally induce anti-inflammatory monocyte and macrophage populations actively promoting resolution of inflammation. Further investigation of these mechanisms should lead to the development of novel therapeutic strategies to modulate undesirable inflammation with fewer side effects via induction of inflammatory resolution rather than non-specific immunosuppression.

Keywords: anti-inflammatory; glucocorticoids; macrophage; monocyte; resolution of inflammation.

Figure 1

Molecular mechanisms of GC action in monocytes and macrophages. Overview of molecular mechanisms involved in regulation of gene expression by GCs in monocytes or macrophages. Specific mechanisms are discussed in the text (numbers 1–15). P, phosphorylation; Ac, acetylation; A, adenosin; U, ubiquitination; TTP, tristetraprolin; ROS, reactive oxygene species.

Figure 2

GC effects on monocyte activation and differentiation. GCs inhibit activation of monocytes by microbial products like LPS but also induce differentiation of an anti-inflammatory monocyte phenotype which produces anti-inflammatory mediators, is protected from apoptosis and shows increased migratory and phagocytic capacities. ROS, reactive oxygene species; NO, nitric oxide; IL-1 RII, IL-1 decoy receptor; FRP, formyl peptide receptor; FPR-L1, formyl peptide receptor like 1.

Figure 3

GC effects on macrophage activation and differentiation. GCs inhibit classical activation of macrophages. When acting on naïve macrophages GCs induce a specific and characteristic phenotype with anti-inflammatory properties. GC actions on other forms of alternative activation of macrophages (IL-4/IL-13, immune complexes (IC) or adenosine receptor ligands) are currently unknown. NO, nitric oxide; IL-1 RII, IL-1 decoy receptor.