Cell surface-anchored SR-PSOX/CXC chemokine ligand 16 mediates firm adhesion of CXC chemokine receptor 6-expressing cells

Shimaoka, Takeshi; Nakayama, Takashi; Fukumoto, Noriko; Kume, Noriaki; Takahashi, Shuntaro; Yamaguchi, Junko; Minami, Manabu; Hayashida, Kazutaka; Kita, Toru; Ohsumi, Jun; Yoshie, Osamu; Yonehara, Shin

doi:10.1189/jlb.1003465

Cited by 206 publications

(187 citation statements)

References 28 publications

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“…Our observation that the E274Q CXCR6 mutant could promote adhesion but not signalling, tallies with results of a previous study, in which pertussis toxin treatment of CXCR6 transfectants was found to ablate chemotactic responses to soluble CXCL16 but not adhesion to the membrane-bound form of CXCL16, highlighting that signalling and adhesion are independent functions of CXCR6 [10]. This is also true for CX3CL1-mediated adhesion [36,37].…”

Section: Discussionsupporting

confidence: 91%

“…Immunohistochemical analysis suggests that CXCL16 is expressed by lipid-laden macrophages in the intima of atherosclerotic plaques and by valvular and neocapillary endothelial cells in patients with infective endocarditis, suggesting a role in the pathogenesis of both diseases [8,9]. Membrane-bound CXCL16 also facilitates the firm adhesion of cells expressing the G protein-coupled receptor CXCR6, such as activated T cells and NKT cells [10]. As a soluble chemokine, CXCL16 promotes chemotaxis via CXCR6, and serves as a chemoattractant for CXCR6 + T cells [2,3].…”

Section: Introductionmentioning

confidence: 99%

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Site‐directed mutagenesis of the chemokine receptor CXCR6 suggests a novel paradigm for interactions with the ligand CXCL16

2008

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Chemokine receptor CXCR6 mediates the chemotaxis and adhesion of leukocytes to soluble and membrane-anchored forms of CXCL16, and is an HIV-1 co-receptor. Here, we describe the effects of mutation of acidic extracellular CXCR6 residues on receptor function. Although most CXCR6 mutants examined were expressed at levels similar to wild-type (WT) CXCR6, an N-terminal E3Q mutant was poorly expressed, which may explain previously reported protective effects of a similar single nucleotide polymorphism, with respect to late-stage HIV-1 infection. In contrast to several other chemokine receptors, mutation of the CXCR6 N terminus and inhibition of post-translational modifications of this region were without effect on receptor function. Likewise, N-terminal extension of CXCL16 resulted in a protein with decent potency and efficacy in chemotaxis and not, as anticipated, a CXCR6 antagonist. D176N and E274Q CXCR6 mutants were unable to interact with soluble CXCL16, suggesting a critical role for D176 and E274 in ligand binding. Intriguingly, although unable to interact with soluble CXCL16, the E274Q mutant could promote robust adhesion to membrane-anchored CXCL16, suggesting that soluble and membrane-bound forms of CXCL16 possess distinct conformations. Collectively, our data suggest a novel paradigm for the CXCR6:CXCL16 interaction, a finding which may impact the discovery of small-molecule antagonists of CXCR6.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Site‐directed mutagenesis of the chemokine receptor CXCR6 suggests a novel paradigm for interactions with the ligand CXCL16

2008

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“…CXCL16 is a chemokine that is reported to be expressed on dendritic cells and macrophages and is important for the recruitment of T cells and natural killer T cells into various tissues and for cell-cell interactions via the CXCR6 counterreceptor (20)(21)(22). CXCL16 also appears to be important in arthritis; however, it has not been studied previously in human nephritis, in either the kidneys or urine.…”

Section: Discussionmentioning

confidence: 99%

“…However, much less is known about the role of CXCL16, which is a chemokine expressed on dendritic cells and macrophages. This chemokine has been shown to be important for the recruitment of T cells into various tissues and for cell-cell interactions via the CXCR6 counterreceptor (20)(21)(22). Although CXCL16 has been suggested to be important in arthritis, its role in immune nephritis is currently unknown.…”

Section: Vcam-1 P-selectin Tnfri and Cxcl16 In Nephritic Urinementioning

confidence: 99%

Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

Xie

Bhaskarabhatla

et al. 2007

Arthritis & Rheumatism

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Objective. Currently, proteinuria is viewed as the earliest indicator of renal disease in immune-mediated nephritis. The objective of this study was to determine whether additional mediators may be excreted in the urine during immune-mediated nephritis, using an experimental model with a well-defined disease course.Methods. Urine samples from mice with antiglomerular basement membrane (anti-GBM) antibodyinduced experimental nephritis were screened using a focused immunoproteome array bearing 62 cytokines/ chemokines/soluble receptors. Molecules identified through this screening assay were validated using an enzyme-linked immunosorbent assay. One of these molecules was further evaluated for its pathogenic role in disease, using antibody-blocking studies.Results. Compared with B6 and BALB/c mice, in which moderately severe immune-mediated nephritis develops, the highly nephritis-susceptible 129/Sv and DBA/1 mice exhibited significantly increased urinary levels of vascular cell adhesion molecule 1 (VCAM-1), P-selectin, tumor necrosis factor receptor I (TNFRI), and CXCL16, particularly at the peak of disease. Whereas some of the mediators appeared to be serum derived early in the disease course, local production in the kidneys appeared to be an important source of these mediators later in the course of disease. Both intrinsic renal cells and infiltrating leukocytes appeared to be capable of producing these mediators. Finally, antibodymediated blocking of CXCL16 ameliorated experimental immune nephritis.Conclusion. These studies identified VCAM-1, P-selectin, TNFRI, and CXCL16 as a quartet of molecules that have potential pathogenic significance; the levels of these molecules are significantly elevated during experimental immune nephritis. The relevance of these molecules in spontaneous immune nephritis warrants investigation.

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“…Protease activity can also modulate the function of the chemokine CX3CL1 that is tethered to the cell surface through a mucin-like stalk. Although it is attached to the cell surface, CX3CL1 acts as a cell adhesion molecule, but after proteolytic cleavage, it functions as a soluble chemokine (5,6). Finally, recent advances reveal the potential for proteases to activate chemoattractants (7,8).…”

mentioning

confidence: 99%

Staphylococcus aureus-Derived Staphopain B, a Potent Cysteine Protease Activator of Plasma Chemerin

Kulig¹,

Zabel

Dubin

et al. 2007

The Journal of Immunology

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Chemerin is an attractant for cells that express the serpentine receptor CMKLR1, which include immature plasmacytoid dendritic cells (pDC) and macrophages. Chemerin circulates in the blood where it exhibits low biological activity, but upon proteolytic cleavage of its C terminus, it is converted to a potent chemoattractant. Enzymes that contribute to this conversion include host serine proteases of the coagulation, fibrinolytic, and inflammatory cascades, and it has been postulated that recruitment of pDC and macrophages by chemerin may serve to balance local tissue immune and inflammatory responses. In this work, we describe a potent, pathogen-derived proteolytic activity capable of chemerin activation. This activity is mediated by staphopain B (SspB), a cysteine protease secreted by Staphylococcus aureus. Chemerin activation is triggered by growth medium of clinical isolates of SspB-positive S. aureus, but not by that of a SspBnull mutant. C-terminal processing by SspB generates a chemerin isoform identical with the active endogenous attractant isolated from human ascites fluid. Interestingly, SspB is a potent trigger of chemerin even in the presence of plasma inhibitors. SspB may help direct the recruitment of specialized host cells, including immunoregulatory pDC and/or macrophages, contributing to the ability of S. aureus to elicit and maintain a chronic inflammatory state.

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Cell surface-anchored SR-PSOX/CXC chemokine ligand 16 mediates firm adhesion of CXC chemokine receptor 6-expressing cells

Cited by 206 publications

References 28 publications

Site‐directed mutagenesis of the chemokine receptor CXCR6 suggests a novel paradigm for interactions with the ligand CXCL16

Site‐directed mutagenesis of the chemokine receptor CXCR6 suggests a novel paradigm for interactions with the ligand CXCL16

Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

Staphylococcus aureus-Derived Staphopain B, a Potent Cysteine Protease Activator of Plasma Chemerin

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