Mouse ChemR23 Is Expressed in Dendritic Cell Subsets and Macrophages, and Mediates an Anti-Inflammatory Activity of Chemerin in a Lung Disease Model This information is current as of September 29, 2021. Souphalone Luangsay, Valérie Wittamer, Benjamin Bondue, Olivier De Henau, Laurie Rouger, Maryse Brait, Jean-Denis Franssen, Patricia de Nadai, François Huaux and Marc Parmentier J Immunol 2009; 183:6489-6499; Prepublished online 19 Downloaded from October 2009; doi: 10.4049/jimmunol.0901037 http://www.jimmunol.org/content/183/10/6489 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2009/10/20/jimmunol.090103 Material 7.DC1 References This article cites 60 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/183/10/6489.full#ref-list-1 by guest on September 29, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! 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The Journal of Immunology Mouse ChemR23 Is Expressed in Dendritic Cell Subsets and Macrophages, and Mediates an Anti-Inflammatory Activity of Chemerin in a Lung Disease Model1 Souphalone Luangsay,2* Vale´rie Wittamer,2* Benjamin Bondue,2* Olivier De Henau,* Laurie Rouger,* Maryse Brait,† Jean-Denis Franssen,† Patricia de Nadai,* Franc¸ois Huaux,‡ and Marc Parmentier3* Chemerin is the ligand of the ChemR23 receptor and a chemoattractant factor for human immature dendritic cells (DCs), macrophages, and NK cells. In this study, we characterized the mouse chemerin/ChemR23 system in terms of pharmacology, structure-function, distribution, and in vivo biological properties. Mouse chemerin is synthesized as an inactive precursor (prochemerin) requiring, as in human, the precise processing of its C terminus for generating an agonist of ChemR23. Mouse Downloaded from ChemR23 is highly expressed in immature plasmacytoid DCs and at lower levels in myeloid DCs, macrophages, and NK cells. Mouse prochemerin is expressed in most epithelial cells acting as barriers for pathogens but not in leukocytes. Chemerin promotes calcium mobilization and chemotaxis on DCs and macrophages and these functional responses were abrogated in ChemR23 knockout mice. In a mouse model of acute lung inflammation induced by LPS, chemerin displayed potent anti-inflammatory properties, reducing neutrophil infiltration and inflammatory cytokine release in a ChemR23-dependent manner. ChemR23 knockout mice were unresponsive to chemerin and displayed an increased neutrophil infiltrate following LPS challenge. Alto- http://www.jimmunol.org/ gether, the mouse chemerin/ChemR23 system is structurally and functionally conserved between human and mouse, and mouse can therefore be considered as a good model for studying the anti-inflammatory role of this system in the regulation of immune responses and inflammatory diseases. The Journal of Immunology, 2009, 183: 6489–6499. uring an inflammatory process, damaged tissues release are the most potent APCs. They are equipped with a set of recep- mediators that contribute to the mounting of immune tors for danger signals, allowing them to adapt their behavior and D responses by regulating the trafficking of leukocyte pop- dictate the outcome of the resulting immune response (3–6). Given ulations. Chemokines and other chemoattractant molecules there- this pivotal position at the intersection of innate and adaptive im- by guest on September 29, 2021 fore play fundamental roles in the physiology of inflammatory munity, DCs are attractive targets for the development of thera- events, as well as in the pathological dysregulations of theses pro- peutic strategies shaping the immune responses in pathological cesses (1, 2). APCs are multifunctional immune effector cells that states such as cancer, inflammatory diseases, and graft rejection act as sentinels, capturing Ags and transporting them to lymphoid (7). Two main categories of DCs have been described, the con- tissues, where they activate naive T cells. Dendritic cells (DCs)4 ventional, or myeloid, DCs (mDCs) and the plasmacytoid DCs (pDCs), which have clearly distinct roles in the initiation of im- munity against specific pathogens (8, 9). mDCs include resident *Institut de Recherche Interdisciplinaire en Biologie Humaine et Mole´culaire, Uni- immature DCs that are found in most peripheral tissues, including versite´Libre de Bruxelles, Campus Erasme, Brussels, Belgium; †Euroscreen, Gosse- lies, Belgium; and ‡Laboratoire de Toxicologie Industrielle, Universite´Catholique de primary and secondary lymphoid organs. In nonlymphoid tissues, Louvain, Brussels, Belgium resident DCs are frequently located in close contact with the mu- Received for publication April 2, 2009. Accepted for publication September 11, 2009. cosal surfaces (respiratory tract, lung, intestine) where they can The costs of publication of this article were defrayed in part by the payment of page directly sample incoming pathogens through the epithelial barrier charges. This article must therefore be hereby marked advertisement in accordance (10). Following maturation, mDCs migrate to the local draining with 18 U.S.C. Section 1734 solely to indicate this fact. lymph nodes. pDCs are recruited directly to lymphoid tissues 1 This work was supported by the Interuniversity Attraction Poles Programme, Bel- through high endothelial venules (11–13). Whereas mDCs display gian State, Belgian Science Policy; the Actions de Recherche Concerte´es of the Com- munaute´ Franc¸aise de Belgique; the European Union (LSHB-CT-2005–518167/ a full battery of chemokine receptors, only a few receptors were INNOCHEM); the Fonds de la Recherche Scientifique Me´dicale of Belgium; the demonstrated to be functional for the recruitment of immature Walloon Region (Programme d’excellence “CIBLES”); The Fonds Ithier; the Fe´de´r- ation Belge contre le Cancer; and the Fondation Me´dicale Reine Elisabeth to pDCs, including CXCR4, CXCR3, and CCR9 (13–17). M.P. B.B. and O.D.H. are aspirants of the Belgian National Fund for Scientific Chemerin is a novel extracellular mediator that we identified as Research. the ligand of ChemR23, a G protein-coupled receptor expressed by 2 These authors contributed equally to this work. immature mDCs and pDCs, NK cells, and macrophages (18–21). 3 Address correspondence and reprint requests to Dr. Marc Parmentier, I.R.I.B.H.M. High amounts of active chemerin were found in various inflam- Universite´Libre de Bruxelles, Campus Erasme, Route de Lennik 808, B-1070, Brus- sels, Belgium. E-mail address: [email protected]. matory situations as in human (rheumatoid arthritis, inflammatory 4 Abbreviations used in this paper: DC, dendritic cell; AM, alveolar macrophage; ascites) and ChemR23-expressing cell recruitment was described BAL, bronchoalveolar lavage; BALF, bronchoalveolar lavage fluid; BMDC, bone in human inflammatory diseases (21, 22). Chemerin was charac- marrow-derived DC; KO, knockout; mDC, myeloid DC; pDC, plasmacytoid DC; terized as a strong chemoattractant factor acting at subnanomolar WT, wild type. concentrations (18, 22). The protein is secreted as an inactive pre- Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 cursor, prochemerin, which is converted into a full agonist of www.jimmunol.org/cgi/doi/10.4049/jimmunol.0901037 6490 MOUSE CHEMERIN/CHEMR23 SYSTEM ChemR23 by proteolytic removal of the last six or seven amino binding assays were normalized for the nonspecific binding (0%) and the acids (23). Extracellular proteases, such as the neutrophil-derived specific binding in the absence of competitor (100%). Binding parameters cathepsin G and elastase, were shown to generate chemerin from were determined with the Prism software using nonlinear regression ap- plied to a one-site competition model. prochemerin, suggesting that the processing takes place at sites of inflammation (24, 25). Indeed, increased chemerin production was Antibodies detected in psoriasis skin (26, 27) and in lupus erythematosus skin mAbs 489C (IgM) and 681 (IgG2ck) directed against the mouse ChemR23 lesions (22), as well as high expression of ChemR23 on pDCs, receptor were obtained following immunization of HsdCpd Wistar Uni- known to play a determinant role in skin inflammatory processes lever rats (Harlan Netherlands) with a peptide corresponding to the second (26, 28). The novel chemerin/ChemR23 system therefore consti- extracellular loop (acetyl-CAPESSPHPAHSQV-amide). tutes an attractive candidate for directing specific DC migration Mouse DC, macrophage, and NK cell preparations under inflammatory conditions. To investigate the role of Mouse BMDCs were generated as previously described (30). Briefly, ChemR23 and its ligand in physiological and pathophysiological BMDCs were recovered by flushing femurs and tibiae and cells were cul- situations, we initiated the study