Collagen Induces Maturation of Human Monocyte-Derived Dendritic Cells by Signaling through Osteoclast-Associated Receptor

Abstract

Osteoclast-associated receptor (OSCAR) is widely expressed on human myeloid cells. Collagen types (Col)I, II, and III have been described as OSCAR ligands, and ColII peptides can induce costimulatory signaling in receptor activator for NF-κB–dependent osteoclastogenesis. In this study, we isolated collagen as an OSCAR-interacting protein from the membranes of murine osteoblasts. We have investigated a functional outcome of the OSCAR–collagen interaction in human monocyte-derived dendritic cells (DCs). OSCAR engagement by ColI/II-induced activation/maturation of DCs is characterized by upregulation of cell surface markers and secretion of cytokines. These collagen-matured DCs (Col-DCs) were efficient drivers of allogeneic and autologous naive T cell proliferation. The T cells expanded by Col-DCs secreted cytokines with no clear T cell polarization pattern. Global RNA profiling revealed that multiple proinflammatory mediators, including cytokines and cytokine receptors, components of the stable immune synapse (namely CD40, CD86, CD80, and ICAM-1), as well as components of TNF and TLR signaling, are transcriptional targets of OSCAR in DCs. Our findings indicate the existence of a novel pathway by which extracellular matrix proteins locally drive maturation of DCs during inflammatory conditions, for example, within synovial tissue of rheumatoid arthritis patients, where collagens become exposed during tissue remodeling and are thus accessible for interaction with infiltrating precursors of DCs.

The integrin–collagen connection – a glue for tissue repair?

“…This receptor has also been shown to have a role in the maturation of human monocyte-derived dendritic cells (Schultz et al, 2015). The protein surfactant D has recently been shown to be an OSCAR ligand (Barrow et al, 2015).…”

“…Polymorphisms in the coding region of the α2 gene ITGA2 have been observed to regulate α2 levels on human platelets (Kuncki and Nugent, 2010); and alleles encoding these variants were found in a separate study to be associated with an increased risk of thrombosis and myocardial (A) Integrin α11β1 in collagen reorganization. α11β1 promotes collagen remodeling, whereas α11 deficiency leads to impaired matrix reorganization (Schultz et al, 2015). (1) Binding of TGF-β to its receptor, induces α-SMA expression and (2) upregulates α11 expression through Smad signaling.…”

“…(A) Integrin α11β1 in collagen reorganization. α11β1 promotes collagen remodeling, whereas α11 deficiency leads to impaired matrix reorganization (Schultz et al, 2015). (1) Binding of TGF-β to its receptor, induces α-SMA expression and (2) upregulates α11 expression through Smad signaling.…”

Structural basis of collagen recognition by human osteoclast-associated receptor and design of osteoclastogenesis inhibitors

“…Moreover, receptor activator of nuclear factor-κB ligand (RANKL) differentiation of monocytes to osteoclasts is increased in the presence of collagen-like peptides (CLPs) and can be inhibited by the addition of OSCAR antibodies (9). The description of OSCAR as a collagen-binding receptor of the LRC family places OSCAR with other collagenbinding proteins of this family, including glycoprotein VI (GPVI), leukocyte-associated Ig-like receptor-1 (LAIR-1), and the putative member LILRB4 (9)(10)(11)(12)(13)(14)(15)(16).…”

Structural basis for collagen recognition by the immune receptor OSCAR

“…4 In the immune system, tissue inflammation was proposed to elicit the exposure of collagens that would then engage OSCAR and stimulate DC maturation. 5 Recently, OSCAR was shown to bind the collagenous domains of pulmonary surfactant protein D to induce tumor necrosis factor-a secretion by inflammatory monocytes. 6 Furthermore, the expression of OSCAR is regulated by atherogenic stimuli in myeloid cells, 7 and by oxidized low-density lipoprotein in vascular endothelial cells, 8 suggesting a role in atherogenesis.…”