Modulation of macrophage differentiation and activation by decoy receptor 3

Abstract

Decoy receptor 3 (DcR3) is a soluble receptor of the tumor necrosis factor receptor superfamily and is readily detected in certain cancer patients. Recently, we demonstrated that DcR3.Fc-treated dendritic cells skew T cell responses to a T helper cell type 2 phenotype. In this study, we further asked its ability to modulate CD14+ monocyte differentiation into macrophages induced by macrophage-colony stimulating factor in vitro. We found that DcR3.Fc was able to modulate the expression of several macrophage markers, including CD14, CD16, CD64, and human leukocyte antigen-DR. In contrast, the expression of CD11c, CD36, CD68, and CD206 (mannose receptor) was not affected in the in vitro culture system. Moreover, phagocytic activity toward immune complexes and apoptotic bodies as well as the production of free radicals and proinflammatory cytokines in response to lipopolysaccharide were impaired in DcR3.Fc-treated monocyte-derived macrophages. This suggests that DcR3.Fc might have potent, suppressive effects to down-regulate the host-immune system.

Decoy receptor 3 (DcR3) induces osteoclast formation from monocyte/macrophage lineage precursor cells

“…33 Moreover, DcR3 can suppress macrophage differentiation from monocytes, but enhance monocyte adhesion. 34,35 The present observation that DcR3 can enhance osteoclast differentiation from monocyte lineages through activation of ERK and p38 MAPK further strengthens the significance of reverse signaling to modulate cell function. Aims for our future experiments include the identification of the target ligands for DcR3 in monocytes/macrophages and the clarification of the evoked reverse signaling in more detail.…”

“…Our previous reports on RANK and DcR3 have indicated additional players by these soluble receptors in the regulation of cell function, and confirmed the concept of reverse signaling. [33][34][35]58 We demonstrated that DcR3 could modulate the differentiation and maturation of DC from CD14 þ monocytes. 33 Moreover, DcR3 can suppress macrophage differentiation from monocytes, but enhance monocyte adhesion.…”

“…22,31,32 Third, we recently observed novel actions of DcR3 in monocytes. These include: (i) the modulation of dendritic cells' (DCs) differentiation and maturation, skewing the immune response from Th1 to Th2, 33 (ii) the modulation of macrophage differentiation and impairment of macrophage function, 34 and (iii) the enhancement of monocyte adhesion. 35 These three actions of DcR3 in monocytes are triggered by reverse signalings, irrelevant to cytokine neutralization, and contributes to suppression of host antitumor immunity.…”

“…29,[36][37][38][39] Since our recent study suggested that DcR3, like other members of the TNFR superfamily, is capable of triggering 'reverse signaling' to modulate monocyte differentiation, [33][34][35] we are interested in this study to understand whether DcR3 has any effects in modulating osteoclastogenesis from monocytes/macrophages.…”

Apoptosis Resistance in Rheumatoid Arthritis Synovial Tissue

“…DcR3 is another member of the TNFR protein superfamily that binds and competitively inhibits FasL, LIGHT (a protein homologous to lymphotoxins, exhibits inducible expression, competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes) and TL1A (encoded by the TNFSF15 gene) [54]. Thus, an anti-DcR3-F C protein was shown to inhibit Fas-induced apoptosis in FLS and DcR3 siRNA increased the susceptibility of FLS to Fas-induced apoptosis [26].…”