Ligation of the FcRγ Chain-Associated Human Osteoclast-Associated Receptor Enhances the Proinflammatory Responses of Human Monocytes and Neutrophils

Merck, Estelle; Gaillard, C.; Scuiller, Mathieu; Scapini, Patrizia; Cassatella, Marco A.; Trinchieri, Giorgio; Bates, Elizabeth E. M.

doi:10.4049/jimmunol.176.5.3149

Cited by 45 publications

(64 citation statements)

References 37 publications

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“…Unlike the DAP12-associated TREM-1 [31, 32], CD300e was not upregulated upon monocyte activation via TLR4 (data not shown), thus resembling the FcRg-associated receptor hOSCAR [27]. CD300e ligation induced a rapid intracellular calcium mobilization, as well as the production of ROS, supporting that this receptor may regulate the microbicidal activity of monocytes [33].…”

Section: Discussionmentioning

confidence: 96%

Functional analysis of the CD300e receptor in human monocytes and myeloid dendritic cells

et al. 2010

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The CD300e surface molecule, originally termed immune receptor expressed by myeloid cells (IREM)-2, was reported to associate with the DNAX-activating protein (DAP) 12 adaptor in co-transfected cells, and is capable of signaling. In the present report, we investigated in detail the function of CD300e in monocytes and myeloid DC (mDC) freshly isolated from peripheral blood of normal blood donors. Upon engagement by an agonistic mAb, CD300e triggered an intracellular calcium mobilization and superoxide anion O À 2 production in monocytes. Activation via CD300e provided survival signals that prevented monocyte and mDC apoptosis, triggered the production of pro-inflammatory cytokines and upregulated the expression of cell surface co-stimulatory molecules in both cell types. Moreover, CD300e activation of mDC enhanced the alloreactive response of naive T cells. Overall, our data formally support the notion that CD300e functions as an activating receptor capable of regulating the innate immune response in myeloid cells.Key words: Cell activation . Cell surface molecules . DC . Monocytes IntroductionA number of surface molecules expressed by myeloid cells are members of multigenic families that include both activating and inhibitory receptors [1,2], which contribute to establish a balance of opposite signals that control the initiation, amplitude and duration of the cell response. Activating receptors have a short cytoplasmic tail with a positively charged amino acid residue within their transmembrane region that allows their association with ITAM-bearing adaptors (e.g. DNAX-activating protein (DAP) 12, FceRIg or CD3z) [3]. Upon ligand recognition and receptor clustering, ITAM become tyrosine phosphorylated and serve as docking sites for Src homology type 2 domaincontaining protein tyrosine kinases such as ZAP-70 or Syk [4,5]. Recruitment and activation of protein tyrosine kinases and downstream effectors regulate calcium mobilization, transcriptional activation, cytokine production, migration, proliferation and/or differentiation [6]. In contrast, inhibitory receptors display a longer cytoplasmic tail characterized by the presence of ITIM. Ligand-induced clustering results in tyrosine phosphorylation of ITIM that act as docking sites for SHP-1, SHP-2 or SHIP. Upon recruitment, tyrosine phosphatases become activated and dephosphorylate key signaling mediators of activation pathways such as Syk, LAT, BLNK/SLP-76, Vav, PI3K and cytoskeletal structures, consequently downregulating the signaling cascade [6][7][8].Ã These authors share equal credit for senior authorship. 722The CD300 or immune receptor expressed by myeloid celsl (IREM) family of myeloid-associated receptors consists of at least five surface molecules that are encoded by genes located on human chromosome 17 (17q25) [9]. CD300c (CMRF-35) was the first identified but has been thus far poorly characterized [10,11]. CD300a (IRp60) was shown to associate with SHP-1 and SHP-2, delivering inhibitory signals in human NK cells, mast cells, eosinophils and granulocyt...

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Section: Discussionmentioning

confidence: 96%

Functional analysis of the CD300e receptor in human monocytes and myeloid dendritic cells

et al. 2010

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“…OSCAR expression in human monocyte-derived DCs (11) and monocytes (30) was suggested to support cell survival in the absence of growth factors via induction of antiapoptotic molecules Bcl-2 and Bcl-x L through PI3K and ERK signaling. In our study, the DCs plated on ColI/II showed prolonged viability in the absence of the essential growth factor, GM-CSF, indicating that OSCAR could play an important role in cell survival.…”

Section: Discussionmentioning

confidence: 99%

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

Schultz

Nitze

Zeuthen

et al. 2015

The Journal of Immunology

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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.

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“…endothelial cells, macrophages, neutrophils, monocytes, and monocyte-derived dendritic cells (17,18). Consequently, OSCAR is likely to contribute to the regulation of a wide variety of cellular functions in different cells, including roles in adhesion, activation and enhancement of proinflammatory cascades, cellular recruitment, and prevention of apoptosis.…”

Section: Significancementioning

confidence: 99%

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

Haywood

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Human osteoclast-associated receptor (OSCAR) is an immunoglobulin (Ig)-like collagen receptor that is up-regulated on osteoclasts during osteoclastogenesis and is expressed in a range of myeloid cells. As a member of the leukocyte receptor complex family of proteins, OSCAR shares a high degree of sequence and structural homology with other collagen receptors of this family, including glycoprotein VI, leukocyte-associated Ig-like receptor-1, and leukocyte Ig-like receptor B4, but recognizes a unique collagen sequence. Here, we present the crystal structures of OSCAR in its free form and in complex with a triple-helical collagen-like peptide (CLP). These structures reveal that the CLP peptide binds only one of the two Ig-like domains, the membrane-proximal domain (domain 2) of OSCAR, with the middle and trailing chain burying a total of 661 Å 2 of solvent-accessible collagen surface. This binding mode is facilitated by the unusual topography of the OSCAR protein, which displays an obtuse interdomain angle and a rotation of domain 2 relative to the membrane-distal domain 1. Moreover, the binding of the CLP to OSCAR appears to be mediated largely by tyrosine residues and conformational changes at a shallow Phe pocket. Furthermore, we investigated CLP peptides as inhibitors of osteoclastogenesis and found that a peptide length of 40 amino acids is required to ensure adequate inhibition of osteoclastogenesis in vitro. These findings provide valuable structural insights into the mode of collagen recognition by OSCAR and into the use of synthetic peptide matrikines for osteoclastogenesis inhibition.C ollagen is a highly versatile family of proteins consisting of more than 28 members that achieve a high degree of complexity through association of different collagen types, the use of multiple transcription initiation sites, alternative splicing patterns, posttranslational modifications, and a wide range of expression patterns (1). Despite this heterogeneity, studies of collagen over the past 60 y have revealed that collagens are commonly found as large fibrillar structures consisting of varying lengths of righthanded triple-helical structures that are formed by association of three left-handed polyproline type II helices with a one-residue stagger (2, 3). Crucial to the formation of these triple helical structures are the repetitive amino acid triplet sequences G-X-Y, of which the most frequently observed triplet is G-P-O, with O representing 4-hydroxyproline (4). In these structures the obligate glycine of the triplet is buried toward the center of the helix and is solvent inaccessible, whereas the X and Y residues are solvent accessible with the latter providing crucial stability to collagen fibrils through interchain hydrogen bonding (3). The diversity of imino and amino acids within these X and Y repetitive sequences are thought to result in changes in the helical parameters of collagen, which vary from a tight left-handed 7 2 to a looser 10 3 helical symmetry, and could provide a more flexible and accessible motif fo...

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Ligation of the FcRγ Chain-Associated Human Osteoclast-Associated Receptor Enhances the Proinflammatory Responses of Human Monocytes and Neutrophils

Cited by 45 publications

References 37 publications

Functional analysis of the CD300e receptor in human monocytes and myeloid dendritic cells

Functional analysis of the CD300e receptor in human monocytes and myeloid dendritic cells

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

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

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