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.

The immune response is a critical regulator of zebrafish retinal pigment epithelium regeneration

“…(27,29,35,67,82)), we demonstrate that inflammation and MΦs/µglia are required for RPE regeneration in vivo. Synthetic GCs, such as dexamethasone, have been widely used to suppress inflammation and do so by attenuating the inflammatory phase post-injury and driving macrophages toward an anti-inflammatory phenotype (87)(88)(89). Results from our study support the existence of a critical inflammatory phase during RPE regeneration, as evidenced by expression of phagocytic (e.g.…”

“…MΦ/µglia infiltration was unaffected and pyknotic nuclei did not accumulate in dexamethasone-treated larvae, indicating intact phagocytic function, yet the outcome was still impaired RPE regeneration. GCs have been shown to have varying effects on macrophage migration (89); indeed, in GC-treated zebrafish post-wounding, leukocyte migration defects have been detected in some injury paradigms (27,35,67), but not others (90,91). Further, GCs have been shown to increase phagocytosis by macrophages to promote expedited resolution of inflammation (87,89), which may explain the lack of pyknotic nuclei accumulation in dexamethasone-treated larvae post-RPE damage.…”

“…GCs have been shown to have varying effects on macrophage migration (89); indeed, in GC-treated zebrafish post-wounding, leukocyte migration defects have been detected in some injury paradigms (27,35,67), but not others (90,91). Further, GCs have been shown to increase phagocytosis by macrophages to promote expedited resolution of inflammation (87,89), which may explain the lack of pyknotic nuclei accumulation in dexamethasone-treated larvae post-RPE damage. Collectively, the results from dexamethasone and irf8 mutant experiments hint at the existence of critical inflammatory and resolution phases post-RPE ablation, and we provide evidence that by-passing either phase results in the same outcome: impairment of RPE regeneration.…”

Mutant glucocorticoid receptor binding elements on Interleukin-6 promoter regulate dexamethasone effects

“…GCs remove endo-and exogenous danger signals by an increased phagocytic capacity, and limit T-cell activation [25].…”

Mutant Glucocorticoid Receptor Binding Elements on the Interleukin-6 Promoter Regulate Dexamethasone Effects

“…The recent evidence revealed that GCs could e ciently inhibit these processes by downregulating pro-in ammatory mediators from macrophages and monocytes and their migration toward in ammatory stimuli. In addition, GCs could remove endo-and exogenous danger signals by increasing phagocytic capacity and limiting T-cell activation [25].…”