Glucocorticoids promote survival of anti-inflammatory macrophages via stimulation of adenosine receptor A3

Abstract

Active resolution of inflammation is a previously unrecognized process essential for tissue homeostasis. Monocytes play a pivotal role in the generation as well as resolution of inflammation. Glucocorticoids (GCs) are widely used antiinflammatory agents. We demonstrate that GCs exhibit antiapoptotic effects in monocytes resulting in differentiation to an anti-inflammatory phenotype. The molecular basis of this novel antiapoptotic effect is a prolonged activation of the extracellular signal regulated kinase/mitogenactivated protein kinase (ERK/MAPK) pathway resulting in inhibition of caspase activities and expression of antiapoptotic genes via activation of c-Myc. We identified up-regulation and activation of A3 adenosine receptor (A3AR) as the initial trigger of this antiapoptotic pathway. In summary, we deciphered a novel molecular pathway promoting survival of anti-inflammatory monocytes. Specific activation of A3AR or its downstream signaling pathways may thus be a novel strategy to modulate inflammation in autoimmune disorders with fewer side effects via induction of inflammatory resolution rather than immunosuppression. IntroductionGlucocorticoids (GC) are very effective anti-inflammatory and immunosuppressive agents widely used in the treatment of many autoimmune and allergic diseases. 1 However, long-term therapy with GCs is associated with substantial side effects that limit their use in many clinical conditions. Thus, novel insights in the molecular mechanisms of GCs action on immune cells are a prerequisite for the development of more specific antiinflammatory therapies. 2 The anti-inflammatory effect of GCs on immune cells was believed to be primarily mediated by interaction with transcriptional factors essential for expression of proinflammatory genes (transrepression). GC-mediated gene expression (transactivation), on the other hand, has been supposed to be responsible for many GC side effects. 3 With respect to monocytes, however, we and other groups demonstrated that GC-mediated gene transcription is crucial for differentiation of an active anti-inflammatory monocytic phenotype. [4][5][6] Monocytes and macrophages are central components of the immune system. During infection and inflammation, they play a pivotal role in the generation of inflammatory mediators and regulation of innate and adaptive immune responses. They also contribute to resolution of inflammation, not only by producing anti-inflammatory cytokines but also by removal of proinflammatory pathogens, cellular debris and apoptotic cells present at later stages of inflammation. 7,8 Thus, monocytes and macrophages do not represent a homogenous cell population, but rather comprise specific subsets with proinflammatory or anti-inflammatory properties depending on their stage of differentiation as well as on distinct mechanisms of activation. [9][10][11] It was generally believed that anti-inflammatory actions of GCs on monocytes and macrophages are mainly due to down-regulation of proinflammatory functions. 12,13 However, analyzing the g...

Glucocorticoid treatment skews human monocyte differentiation into a hemoglobin-clearance phenotype with enhanced heme-iron recycling and antioxidant capacity

“…The enhanced CD163 expression was found to be in agreement with a general M2 transcriptome polarization, which characterizes an anti-inflammatory macrophage phenotype considered to be involved in the down-regulation of acute inflammation and wound healing. [24][25][26][27][28][29] Upon concurrent treatment with dexamethasone and Hb:Hp, the monocyte proteome shifted toward a signature consistent with enhanced endocytosis of Hb:Hp, enhanced heme breakdown by HO-1 and storage of Hb-derived iron within ferritin, and cellular exclusion of transferrin iron. These changes reflect a major gain-of-function effect of glucocorticoids that supports a very specific homeostatic role of monocytes.…”

“…M2 signature genes (ie, the interleukin-1 decoy-receptor, mannose receptor, and arginase) and/or genes known to be highly induced by glucocorticoids (ie, adenosine A3 receptor and FK506 binding protein) have been compiled from the literature and are highlighted alongside with down-regulated M1 signature genes such as the chemokines interleukin-8 and CXCL10 and indoleamine 2,3 dioxygenase. [24][25][26][27][28][29] Simultaneous glucocorticoid treatment and Hb:Hp exposure induces antioxidant and iron recycling genes After establishing that dexamethasone promotes a monocyte phenotype with activated Hb clearance capacity, we performed 2 different gene array experiments to analyze the interactive effects of concurrent glucocorticoid treatment and Hb:Hp exposure on the monocyte transcriptome. This simultaneous exposure of monocytes to extracellular Hb and glucocorticoids is similar to that experienced during treatment of hemolysis.…”

Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21

“…The gene networks generated from M2/2.WT cells indicated ERK 1/2 as the main regulatory hub (P value 5 10 240 , 34 molecules), whereas the top predicted network generated from cells lacking pTyr-721 was centered on NF-kB (P value 5 10 236 , 30 molecules; supplemental Table 4), both of which have been linked to regulation of inflammation [48][49][50][51][52] and macrophage polarization. [51][52][53] Additional data mining on gene expression signatures previously associated with the CSF-1-mediated macrophage shift toward an M2 phenotype in 54,55 identified a significant overlap in gene identity and direction of regulation between the 96 genes differentially expressed in M1 vs M2 polarized macrophages 54 and 19 of our pTyr-721-regulated transcripts (supplemental Figure 2D).…”

Transcriptome Assessment Reveals a Dominant Role for TLR4 in the Activation of Human Monocytes by the Alarmin MRP8

“…Monocytes were treated as described previously (36). Monocytes prestimulated with MRP8 were treated with 400 nM staurosporine for an additional 6 h or were left untreated.…”