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Chemotaxis to CX3CL1 (Fractalkine) Syk Is Required for Monocyte/Macrophage

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Chemotaxis to CX3CL1 (Fractalkine) Syk Is Required for Monocyte/Macrophage Syk Is Required for Monocyte/Macrophage Chemotaxis to CX3CL1 (Fractalkine) Jean-Claude Gevrey, Beth M. Isaac and Dianne Cox This information is current as J Immunol 2005; 175:3737-3745; ; of September 26, 2021. doi: 10.4049/jimmunol.175.6.3737 http://www.jimmunol.org/content/175/6/3737 Downloaded from References This article cites 59 articles, 36 of which you can access for free at: http://www.jimmunol.org/content/175/6/3737.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 26, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Syk Is Required for Monocyte/Macrophage Chemotaxis to CX3CL1 (Fractalkine)1 Jean-Claude Gevrey,2* Beth M. Isaac,* and Dianne Cox*† CX3CL1 (fractalkine), the only member of the ␦ subclass of chemokines, is a known chemotactic factor for monocytes/macro- phages as well as NK cells and T lymphocytes. In several pathologies, excessive production of CX3CL1 at specific sites leads primarily to monocyte/macrophage recruitment, which causes tissue and vascular damage. Despite their clinical relevance, the mechanisms underlying monocyte/macrophage chemotaxis to CX3CL1 remain poorly documented. The present report addresses this issue and identifies cell signaling crucial for this process. Using the murine monocyte/macrophage RAW cell line, we show that CX3CL1 treatment elicits a rapid and transient increase in F-actin and the formation of F-actin-enriched cell protrusions. CX3CL1 also triggers tyrosine phosphorylation of proteins localized in those protrusions. The protein tyrosine kinase Syk is activated upon CX3CL1 treatment, and reduction of Syk expression using RNA-mediated interference results in a specific and Downloaded from massive impairment of RAW cell migration to CX3CL1. Similar results are obtained using the Syk inhibitor, piceatannol. Cells with reduced Syk expression also exhibit a major defect in CX3CL1-induced cytoskeletal remodeling. These data suggest that in monocytes/macrophages, Syk is essential for proper reorganization of the actin cytoskeleton in response to CX3CL1 and is therefore required for cell chemotaxis to CX3CL1. The Journal of Immunology, 2005, 175: 3737–3745. lso known as fractalkine or neurotactin, CX3CL1 is as of marked decrease in monocyte/macrophage accumulation com- http://www.jimmunol.org/ now the only member of the ␦/CX3C subclass of che- pared with CX3CR1ϩ/ϩ animals (8, 9). Also, soluble CX3CL1 is A mokines, established on the basis of the arrangement of up-regulated in the synovial fluid of rheumatoid arthritis patients N-terminal conserved cysteine residues (1, 2). In vivo, CX3CL1 and induces the migration of CX3CR1-expressing monocytes (4). appears to be expressed by a variety of tissues and cell types. In Despite the clinical relevance of the interaction between cells of particular, it is found as a transmembrane-anchored molecule at the the monocyte/macrophage lineage and CX3CL1, there is no infor- surface of endothelial cells activated with inflammatory cytokines, mation available regarding the mechanisms underlying their ability where it behaves as an adhesion molecule. When released from the to chemotax toward this molecule. Using the MonoMac6 cell line cell surface through proteolytic cleavage, the soluble domain of in response to soluble CX3CL1, Cambien et al. (11) have identi- CX3CL1 acts as a chemotactic factor for monocytes, NK cells, and fied PI3K and members of the MAPK family, ERK1/2, p38MAPK, by guest on September 26, 2021 T cells (1, 2). CX3CL1 binds exclusively the cell surface, seven- and JNK1, as signaling components required for cell adhesion to transmembrane, G protein-coupled receptor CX3CR1 and repre- fibronectin. Activation of Src and phosphorylation of Syk tyrosine sents its sole cognate ligand to date (3). kinases downstream of CX3CR1 have also been reported, although Originally considered a homeostatic chemokine involved in a putative functional role for these enzymes in any CX3CL1-in- basal trafficking/homing of leukocytes, CX3CL1 is now increas- duced cell response has not been investigated (11). Surprisingly, ingly recognized as a molecule whose expression is enhanced un- MonoMac6 cells fail to achieve chemotaxis or transendothelial der particular pathological situations, causing an excessive recruit- migration in response to CX3CL1 (12). The THP-1 monocytic cell ment of cytotoxic leukocytes and therefore extensive vascular and line, also used in studies addressing the mechanism of CX3CL1- tissue injury. Recently, accumulating evidence has indicated a role for CX3CL1 in the pathogenesis of a number of diseases, includ- dependent cell adhesion (13), has similarly been reported to have ing, but not limited to, rheumatoid arthritis (4–6) and atheroscle- a negligible chemotactic response to CX3CL1 (14). These obser- rosis (7–10). Interestingly, mononuclear phagocytes represent the vations indicate that MonoMac6 and THP-1 cell lines, both estab- key component of the cellular infiltrates in those two cases, and lished from an acute monocytic leukemia patient, do not mimic the their recruitment in response to CX3CL1 has been shown to sig- behavior of monocytes/macrophages in vivo or freshly isolated nificantly contribute to the extent of the disease. Indeed, monocytes as far as chemotaxis toward CX3CL1 is concerned (1, CX3CR1Ϫ/Ϫ mice placed into an atherosclerosis-prone back- 8, 9, 15–17). The reasons for this apparent discrepancy are ground have reduced atherosclerotic lesion formation as well as a unknown. Using cells derived from the murine monocyte/macrophage RAW 264.7 cell line, we aimed at identifying signaling compo- *Department of Anatomy and Structural Biology and †Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461 nents required for cell migration in response to soluble CX3CL1. Received for publication February 23, 2005. Accepted for publication July 12, 2005. In the present report we provide evidence that these cells represent a valuable model to study CX3CL1-induced chemotaxis and ex- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance hibit morphological changes and remodeling of the actin cytoskel- with 18 U.S.C. Section 1734 solely to indicate this fact. eton upon CX3CL1 treatment. Because tyrosine phosphorylation 1 This work was supported by Grant KO1AR02158 from the National Institutes of has been reported to be important in the function of several che- Health (to D.C.). mokine receptors, we explored this possibility with respect to 2 Address correspondence and reprint requests to Dr. Jean-Claude Gevrey, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Gruss/MRRC Room 306, CX3CR1-mediated cell chemotaxis. We show that the cytoplasmic Bronx, NY 10461. E-mail address: [email protected] protein tyrosine kinase Syk is rapidly activated by CX3CL1, and Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 3738 Syk IN CX3CL1 CHEMOTAXIS using RNA-mediated interference to reduce endogenous Syk lev- fixation and permeabilization as described in Immunofluorescence micros- els, we show that Syk is required for proper formation of mem- copy above. Fixed cells were incubated with saturating concentrations of brane protrusions and cell chemotaxis in response to CX3CL1. Our rhodamine-phalloidin and YO-PRO-1 (both from Molecular Probes) to stain F-actin and nucleic acids, respectively. Fluorescence intensities of data demonstrate a new function of Syk downstream of a chemo- rhodamine (excitation wavelength, 545 nm; emission wavelength, 590 nm) kine receptor besides its well-documented roles in signal transduc- and YO-PRO-1 (excitation wavelength, 485 nm; emission wavelength, 520 tion from immunoreceptors and integrins in hemopoietic cells. nm) were measured using a plate reader (Polarstar Optima), and the nor- malized F-actin cellular content (calculated as the ratio of rhodamine to YO-PRO-1 fluorescence) was expressed as the percent increase in response Materials and Methods to CX3CL1 compared with the unstimulated condition. Cells, Abs, and reagents RAW/LR5 cells (RAW), derived from the murine monocyte/macrophage Immunoprecipitation and Western blotting RAW 264.7 cell line, have been described previously (18) and were cul- tured in RPMI 1640 medium (Mediatech) supplemented with 10% heat- Cells were lysed in ice-cold buffer A containing 25 mM Tris, 137 mM inactivated FBS (Sigma-Aldrich) and antibiotics (100 IU/ml penicillin/100 NaCl, 1% Triton X-100, 1% SDS, 2 mM EDTA, 1 mM orthovanadate, 1 ␮g/ml streptomycin). Murine bone marrow-derived macrophages were iso- mM benzamidine, 10 ␮g/ml aprotinin, and 10 ␮g/ml leupeptin, pH 7.4. For lated and prepared as previously described (19) and were cultured in immunoprecipitation, the SDS concentration of the total cell lysate was ␣-MEM supplemented with 15% FBS, 360 ng/ml recombinant human lowered to Ͻ0.2% by dilution in buffer A without SDS before incubation CSF-1 (Chiron), and antibiotics. All cells were maintained at 37°C in a 5% with Abs prebound to Protein A/G Plus agarose beads (Santa Cruz Bio- CO2 atmosphere. Recombinant mouse CX3CL1 (aa 25–105) and mouse technology) overnight at 4°C. Beads were then pelleted, washed three CSF-1 were purchased from R&D Systems. Rabbit anti-CX3CR1 Ab times, resuspended in Laemmli buffer, and boiled for 5 min.
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