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...

Summary CD163 is a multi-ligand scavenger receptor exclusively expressed by monocytes and macrophages, which is released after their activation during sepsis (sCD163F1) of fibronectin (FN) bound to staphylococcal surface molecules. Moreover, contact with staphylococci promotes sCD163-shedding from monocyte surface via induction of metalloproteinases ADAM10 and ADAM17. sCD163 subsequently binds to Staphylococcus aureus via FN peptides and strongly amplifies phagocytosis as well as killing by monocytes and to a lesser extend by neutrophils. This mechanism exhibits additional paracrine effects because staphylococci additionally opsonized by sCD163 induce higher activation and more efficient killing activity of non-professional phagocytes like endothelial cells. Targeting pathogen-bound FN by sCD163 would be a very sophisticated strategy to attack S. aureus as any attempt of the pathogen to avoid this defence mechanism will automatically bring about loss of adherence to the host protein FN, which is a pivotal patho-mechanism of highly invasive staphylococcal strains. Thus, we report a novel function for sCD163 that is of particular importance for immune defence of the host against S. aureus infections.

SummaryBinding to fibronectin (FN) is a crucial pathogenic factor of Staphylococcus aureus mediated by fibronectin-binding protein A (FnBP-A) and extracellular adherence protein (Eap). Recently, we have shown that binding of soluble CD163 (sCD163) to FN linked to these molecules exhibits anti-microbial effects by enhancing phagocytosis and killing activity of S. aureus-infected monocytes. However, it remained unclear whether sCD163 also influences the monocytic activation status. Using genetically modified staphylococcal strains we now identified FnBP-A, but not Eap, as activator of the inflammatory response of monocytes to infection. FnBP-A-mediated inflammatory activation was masked by sCD163 binding to S. aureus promoting efficient pathogen elimination. Thus, sCD163 protects monocytes from overwhelming activation upon staphylococcal infection by dampening the secretion of pro-inflammatory cytokines TNFα, IL-1β, IL-6 and IL-8 and DAMP molecule MRP8/14. Moreover, sCD163 limited expression of pro-apoptotic transcription factor NR4A1 induced during S. aureus infection and inhibited induction of chemokine CXCL2 promoting survival of staphylococci in vivo. sCD163-mediated effects were not due to general immunosuppression since MAP kinase activation and ROS production were unaltered during infection of monocytes with sCD163-bound bacteria. Thus, sCD163 promotes a specific defence of the immune system against FnBP-A-mediated inflammatory activation enabling successful pathogen elimination, tissue recovery and resolution of inflammation.