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Coupled Receptor Kinase 2 Translocation − Chemotaxis By TLR4 Signaling Augments Monocyte Chemotaxis by Regulating G Protein− Coupled Receptor Kinase 2 Translocation This information is current as Zheng Liu, Yong Jiang, Yuehua Li, Juan Wang, Liyan Fan, of September 29, 2021. Melanie J. Scott, Guozhi Xiao, Song Li, Timothy R. Billiar, Mark A. Wilson and Jie Fan J Immunol published online 14 June 2013 http://www.jimmunol.org/content/early/2013/06/14/jimmun ol.1300790 Downloaded from 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 29, 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 Errata An erratum has been published regarding this article. Please see next page or: /content/191/5/2847.full.pdf The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published June 14, 2013, doi:10.4049/jimmunol.1300790 The Journal of Immunology TLR4 Signaling Augments Monocyte Chemotaxis by Regulating G Protein–Coupled Receptor Kinase 2 Translocation Zheng Liu,*,† Yong Jiang,* Yuehua Li,† Juan Wang,*,† Liyan Fan,‡ Melanie J. Scott,† Guozhi Xiao,x Song Li,{ Timothy R. Billiar,†,‖ Mark A. Wilson,†,# and Jie Fan†,‖,# Monocytes are critical effector cells of the innate immune system that protect the host by migrating to inflammatory sites, differ- entiating to macrophages and dendritic cells, eliciting immune responses, and killing pathogenic microbes. MCP-1, also known as CCL2, plays an important role in monocyte activation and migration. The chemotactic function of MCP-1 is mediated by binding to the CCR2 receptor, a member of the G protein–coupled receptor (GPCR) family. Desensitization of GPCR chemokine receptors is an important regulator of the intensity and duration of chemokine stimulation. GPCR kinases (GRKs) induce GPCR phosphor- Downloaded from ylation, and this leads to GPCR desensitization. Regulation of subcellular localization of GRKs is considered an important early regulatory mechanism of GRK function and subsequent GPCR desensitization. Chemokines and LPS are both present during Gram-negative bacterial infection, and LPS often synergistically exaggerates leukocyte migration in response to chemokines. In this study, we investigated the role and mechanism of LPS–TLR4 signaling on the regulation of monocyte chemotaxis. We demonstrate that LPS augments MCP-1–induced monocyte migration. We also show that LPS, through p38 MAPK signaling, induces phosphorylation of GRK2 at serine 670, which, in turn, suppresses GRK2 translocation to the membrane, thereby http://www.jimmunol.org/ preventing GRK2-initiated internalization and desensitization of CCR2 in response to MCP-1. This results in enhanced monocyte migration. These findings reveal a novel function for TLR4 signaling in promoting innate immune cell migration. The Journal of Immunology, 2013, 191: 000–000. onocytes are critical effector cells of the innate immune MCP-1, also known as CCL2, is a 13-kDa chemokine that plays system that protect the host by migrating to inflam- an important role in monocyte activation and migration (4). MCP-1 M matory sites, differentiating to macrophages and den- is released from both hematopoietic and nonhematopoietic cells, dritic cells, eliciting immune responses, and killing pathogenic including monocytes/macrophages, dendritic cells, astrocytes, microbes (1, 2). Monocyte migration is tightly regulated by sig- endothelial cells, and fibroblasts (5). MCP-1 derived from these by guest on September 29, 2021 naling mechanisms activated by chemokines, which act through MCP-1-produce cells contributes to the migration of monocytes chemokine receptors to direct monocyte migration along a con- into local tissue and organ during infection and inflammation (6). centration gradient (3). The physiological function of MCP-1 is mediated by binding to the CCR2 receptor, a member of the G protein–coupled receptor (GPCR) family (7). *Department of Pathophysiology, Southern Medical University, Guangzhou 510515, Desensitization of the GPCR family of chemokine receptors is China; †Department of Surgery, University of Pittsburgh School of Medicine, Pitts- burgh, PA 15213; ‡University of Pittsburgh School of Arts and Science, Pittsburgh, an important determinant of the intensity and duration of agonist PA 15213; xDepartment of Biochemistry, Rush University Medical Center, Chicago, stimulation (8, 9). Receptor desensitization regulates the number { IL 60612; Department of Pharmaceutical Sciences, Center for Pharmacogenetics, of migrating cells, as well as their motility and ability to stop upon University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261; ||McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219; contact with pathogens or target cells (8). G protein–coupled re- and #Research and Development, Veterans Affairs Pittsburgh Healthcare System, ceptor kinases (GRKs) induce GPCR phosphorylation and, thereby, Pittsburgh, PA 15240 signal GPCR desensitization (10). GRKs constitute a family of Received for publication March 22, 2013. Accepted for publication May 8, 2013. seven mammalian serine and threonine protein kinases (11, 12). This work was supported by National Institutes of Health Grant R01-HL-079669 (to GRK2 is a member of the GRK family that was shown to modulate J.F. and M.A.W.), National Institutes of Health Center Grant P50-GM-53789 (to T.R.B. and J.F.), National Institutes of Health Grant R01-GM-50441 (to T.R.B.), a Veterans a variety of functions in leukocytes (13). Activity of GRKs is tightly Affairs Merit Award (to J.F.), National Key Basic Research (973) Program of China regulated by three mechanisms: subcellular localization, alterations 2011CB510200 (to Y.J.), National Natural Science Foundation of China 81030055 (to in intrinsic kinase activity, and alterations in GRK expression (14). Y.J.), Natural Science Foundation of China-Guangdong Joint Fund U0632004 (to Y.J.), and Program for Changjiang Scholars and Innovative Research Team in University Therefore, regulation of GRK subcellular localization represents IRT0731 (to Y.J.). a logical means of regulating monocyte migration. However, the The contents do not represent the views of the Department of Veterans Affairs or the regulation of subcellular localization of GRKs in monocytes and U.S. Government. their effects on monocytes behavior remain unknown. Address correspondence and reprint requests to Dr. Jie Fan or Dr. Yong Jiang, De- LPS, a component of the outer membrane of Gram-negative partment of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (J.F.) or Department of Pathophysiology, Southern Medical University, Guang- bacteria, is a specific ligand for TLR4 and induces a range of in- zhou 510515, China (Y.J.). E-mail addresses: [email protected] (J.F.) or jiang48231@163. flammatory responses, including production of proinflammatory com (Y.J.) mediators and induction of migration of innate immune cells to the Abbreviations used in this article: BALF, bronchoalveolar lavage fluid; BMDM, bone site of infection (15). In this study, we investigated the role and marrow–derived monocyte; GPCR, G protein–coupled receptor; GRK, G protein– coupled receptor kinase; i.t., intratracheal(ly); siRNA, small interfering RNA; WT, mechanism of LPS–TLR4 signaling in regulating monocyte chemo- wild-type. taxis. We demonstrate that LPS augments MCP-1–induced monocyte www.jimmunol.org/cgi/doi/10.4049/jimmunol.1300790 2 TLR4 ACTING THROUGH GRK2 AUGMENTS MONOCYTE CHEMOTAXIS migration. We also show that LPS, through p38 MAPK signaling, monocytes were preincubated with a variety of MAPK inhibitors: p38 induces phosphorylation of GRK2 at Ser670, which, in turn, sup- inhibitor SB203580 (10 mM; Cell Signaling Technology, Boston, MA), presses GRK2 translocation to the membrane, thereby preventing ERK inhibitor PD98059 (50 mM; Cell Signaling Technology) (19), or JNK inhibitor SP600125 (10 mM; Sigma-Aldrich) for 30 min (20). The chamber GRK2-initiated internalization and desensitization of CCR2 in re- was incubated in humidified air with 5% CO2 at 37˚C for the time indi- sponse to MCP-1. This results in enhanced monocyte migration. cated. At the end of experiment, the membrane between the upper and These findings reveal a novel function for TLR4 signaling in pro- lower wells was fixed and stained with Wright–Giemsa stain (Sigma- moting innate immune cell migration. Aldrich). Cell migration was determined by counting the number of cells that had migrated through the filter in three random high-power microscope fields (3400). A chemotactic index was used to express chemotactic ac- Materials and Methods tivity and was calculated as the number of monocytes that migrated across Animals the membrane/number of monocytes that migrated spontaneously toward blank medium in the control group. All experiments were performed in Male C57BL/6 wild-type (WT) mice were purchased from The Jackson triplicate. Laboratory (Bar Harbor, ME). TLR4-knockout (TLR42/2)miceona
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