The CD157-Integrin Partnership Controls Transendothelial Migration and Adhesion of Human Monocytes
2011; Elsevier BV; Volume: 286; Issue: 21 Linguagem: Inglês
10.1074/jbc.m111.227876
ISSN1083-351X
AutoresNicola Lo Buono, Rossella Parrotta, Simona Morone, Paola Bovino, Giulia Nacci, Erika Ortolan, Alberto L. Horenstein, Alona Inzhutova, Enza Ferrero, Ada Funaro,
Tópico(s)Lipid Membrane Structure and Behavior
ResumoCD157, a member of the CD38 gene family, is an NAD-metabolizing ectoenzyme and a signaling molecule whose role in polarization, migration, and diapedesis of human granulocytes has been documented; however, the molecular events underpinning this role remain to be elucidated. This study focused on the role exerted by CD157 in monocyte migration across the endothelial lining and adhesion to extracellular matrix proteins. The results demonstrated that anti-CD157 antibodies block monocyte transmigration and adhesion to fibronectin and fibrinogen but that CD157 cross-linking is sufficient to overcome the block, suggesting an active signaling role for the molecule. Consistent with this is the observation that CD157 is prevalently located within the detergent-resistant membrane microdomains to which, upon clustering, it promotes the recruitment of β1 and β2 integrin, which, in turn, leads to the formation of a multimolecular complex favoring signal transduction. This functional cross-talk with integrins allows CD157 to act as a receptor despite its intrinsic structural inability to do so on its own. Intracellular signals mediated by CD157 rely on the integrin/Src/FAK (focal adhesion kinase) pathway, resulting in increased activity of the MAPK/ERK1/2 and the PI3K/Akt downstream signaling pathways, which are crucial in the control of monocyte transendothelial migration. Collectively, these findings indicate that CD157 acts as a molecular organizer of signaling-competent membrane microdomains and that it forms part of a larger molecular machine ruled by integrins. The CD157-integrin partnership provides optimal adhesion and transmigration of human monocytes. CD157, a member of the CD38 gene family, is an NAD-metabolizing ectoenzyme and a signaling molecule whose role in polarization, migration, and diapedesis of human granulocytes has been documented; however, the molecular events underpinning this role remain to be elucidated. This study focused on the role exerted by CD157 in monocyte migration across the endothelial lining and adhesion to extracellular matrix proteins. The results demonstrated that anti-CD157 antibodies block monocyte transmigration and adhesion to fibronectin and fibrinogen but that CD157 cross-linking is sufficient to overcome the block, suggesting an active signaling role for the molecule. Consistent with this is the observation that CD157 is prevalently located within the detergent-resistant membrane microdomains to which, upon clustering, it promotes the recruitment of β1 and β2 integrin, which, in turn, leads to the formation of a multimolecular complex favoring signal transduction. This functional cross-talk with integrins allows CD157 to act as a receptor despite its intrinsic structural inability to do so on its own. Intracellular signals mediated by CD157 rely on the integrin/Src/FAK (focal adhesion kinase) pathway, resulting in increased activity of the MAPK/ERK1/2 and the PI3K/Akt downstream signaling pathways, which are crucial in the control of monocyte transendothelial migration. Collectively, these findings indicate that CD157 acts as a molecular organizer of signaling-competent membrane microdomains and that it forms part of a larger molecular machine ruled by integrins. The CD157-integrin partnership provides optimal adhesion and transmigration of human monocytes. IntroductionEctoenzymes include a heterogeneous group of surface molecules with multiple functions. In addition to interacting with specific substrates, many of them participate in leukocyte activation and migration. In some cases, ectoenzymes exert enzymatic control of leukocyte trafficking (1Salmi M. Jalkanen S. Nat. Rev. Immunol. 2005; 5: 760-771Crossref PubMed Scopus (221) Google Scholar). Other functions are independent of their enzymatic ability, relying on the activation of signaling cascades that lead to calcium fluxes, cytoskeletal remodeling, and release of inflammatory mediators (2Airas L. Niemelä J. Jalkanen S. J. Immunol. 2000; 165: 5411-5417Crossref PubMed Scopus (66) Google Scholar, 3Mina-Osorio P. Winnicka B. O'Conor C. Grant C.L. Vogel L.K. Rodriguez-Pinto D. Holmes K.V. Ortega E. Shapiro L.H. J. Leukoc. Biol. 2008; 84: 448-459Crossref PubMed Scopus (53) Google Scholar). In selected cases, ectoenzymes associate with adhesion molecules to regulate their signaling (4Ossowski L. Aguirre-Ghiso J.A. Curr. Opin. Cell Biol. 2000; 12: 613-620Crossref PubMed Scopus (355) Google Scholar, 5Frasca L. Fedele G. Deaglio S. Capuano C. Palazzo R. Vaisitti T. Malavasi F. Ausiello C.M. Blood. 2006; 107: 2392-2399Crossref PubMed Scopus (101) Google Scholar).Along with CD38, human CD157 constitutes the NAD glycohydrolase/ADP-ribosyl cyclase gene family (6Ferrero E. Malavasi F. J. Leukoc. Biol. 1999; 65: 151-161Crossref PubMed Scopus (66) Google Scholar). These two molecules share 36% of their protein sequence, including 10 cysteine residues forming intrachain disulfide bonds. However, they differ in structure, with CD157 being a glycosylphosphatidylinositol (GPI) 5The abbreviations used are: GPI, glycosylphosphatidylinositol; F(ab′)2 RαMIgG, F(ab′)2 fraction of rabbit antibodies to mouse IgG; mIgG, mouse monoclonal IgG; FN, fibronectin; Ctx, cholera toxin β-subunit; MCP-1, monocyte chemoattractant protein-1; HPMEC, human pulmonary microvascular endothelial cell line; ECM, extracellular matrix protein; FAK, focal adhesion kinase; TMI, transmigration index. -anchored glycoprotein and CD38 being a transmembrane type II glycoprotein (7Malavasi F. Deaglio S. Funaro A. Ferrero E. Horenstein A.L. Ortolan E. Vaisitti T. Aydin S. Physiol. Rev. 2008; 88: 841-886Crossref PubMed Scopus (588) Google Scholar). CD157 is mainly expressed by cells of the myeloid lineage, bone marrow stroma, and vascular endothelium (8Ortolan E. Vacca P. Capobianco A. Armando E. Crivellin F. Horenstein A. Malavasi F. Cell Biochem. Funct. 2002; 20: 309-322Crossref PubMed Scopus (48) Google Scholar). CD157 is also expressed by ovarian cancer epithelium and by peritoneal mesothelial cells, where it is implicated in tumor dissemination (9Ortolan E. Arisio R. Morone S. Bovino P. Lo-Buono N. Nacci G. Parrotta R. Katsaros D. Rapa I. Migliaretti G. Ferrero E. Volante M. Funaro A. J. Natl. Cancer Inst. 2010; 102: 1160-1177Crossref PubMed Scopus (45) Google Scholar). Further, it is endowed with receptor-like features observed in different cell types (10Ishihara K. Hirano T. Chem. Immunol. 2000; 75: 235-255Crossref PubMed Google Scholar) and transduces signals by interacting with transmembrane partner molecules (11Funaro A. Ortolan E. Ferranti B. Gargiulo L. Notaro R. Luzzatto L. Malavasi F. Blood. 2004; 104: 4269-4278Crossref PubMed Scopus (63) Google Scholar, 12Lavagno L. Ferrero E. Ortolan E. Malavasi F. Funaro A. J. Biol. Regul. Homeost. Agents. 2007; 21: 5-11PubMed Google Scholar), a strategy shared by other GPI-anchored molecules (13Todd 3rd, R.F. Petty H.R. J. Lab. Clin. Med. 1997; 129: 492-498Abstract Full Text PDF PubMed Scopus (93) Google Scholar).CD157 is involved in neutrophil polarization, adhesion, and motility (11Funaro A. Ortolan E. Ferranti B. Gargiulo L. Notaro R. Luzzatto L. Malavasi F. Blood. 2004; 104: 4269-4278Crossref PubMed Scopus (63) Google Scholar) and controls transendothelial migration (14Ortolan E. Tibaldi E.V. Ferranti B. Lavagno L. Garbarino G. Notaro R. Luzzatto L. Malavasi F. Funaro A. Blood. 2006; 108: 4214-4222Crossref PubMed Scopus (38) Google Scholar). This study extends the analysis of the functional role of CD157 to human monocytes, adopted as a physiological model in which to explore the molecular mechanism underlying the role of the molecule in the control of cell motility.Monocytes play key functions in innate and adaptive immunity, immune surveillance, host defense, and inflammation (15Yona S. Jung S. Curr. Opin. Hematol. 2010; 17: 53-59Crossref PubMed Scopus (184) Google Scholar). Furthermore, monocyte trafficking is a critical factor in inflammatory and autoimmune diseases, such as atherosclerosis, multiple sclerosis, and rheumatoid arthritis (16Ross R. N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (19071) Google Scholar).Monocytes originate from hematopoietic precursors in the bone marrow and circulate in the blood for 24–48 h before extravasating into the connective tissues. In inflammation, monocytes are recruited to the affected tissues, where they differentiate into macrophages and dendritic cells (17Kamei M. Carman C.V. Curr. Opin. Hematol. 2010; 17: 43-52Crossref PubMed Scopus (65) Google Scholar). The continuous traffic from blood to tissue and from tissue to lymph nodes relies on orchestrated sequential interactions between leukocytes and vascular or lymphatic endothelium (18Springer T.A. Cell. 1994; 76: 301-314Abstract Full Text PDF PubMed Scopus (6373) Google Scholar). Each step is a prerequisite for the next one. Cell adhesion molecules (such as selectins and integrins) have well established roles in supporting tethering, rolling, and firm adhesion to the vascular endothelium (19Luster A.D. Alon R. von Andrian U.H. Nat. Immunol. 2005; 6: 1182-1190Crossref PubMed Scopus (917) Google Scholar). Chemokines and selected molecules at the endothelial junctions (including CD31, JAM-1, vascular endothelial cadherin, and CD99) are critical in the control of the transmigration process (20Vestweber D. Immunol. Rev. 2007; 218: 178-196Crossref PubMed Scopus (237) Google Scholar). These central components are flanked by an increasing number of molecules from different families, which contribute to distinct steps of the extravasation cascade (21Ley K. Laudanna C. Cybulsky M.I. Nourshargh S. Nat. Rev. Immunol. 2007; 7: 678-689Crossref PubMed Scopus (3015) Google Scholar).The results obtained in this study indicate that CD157 is involved in the control of monocyte extravasation and adhesion to ECM proteins. CD157 establishes a structural interaction with β1 and β2 integrin and, following antibody-induced cross-linking, it promotes their relocation into detergent-resistant domains, thus driving the dynamic reorganization of signaling-competent membrane microdomains. Moreover, CD157 effectively contributes to the integrin-driven signaling network that is critical during monocyte transmigration.DISCUSSIONMonocyte recruitment to extravascular sites is an important component of the inflammatory response to a variety of stimuli such as bacterial infections, tumor growth, and atherosclerotic plaque formation. The surface expression and release (as soluble proteins or membrane vesicles) (34Théry C. Ostrowski M. Segura E. Nat. Rev. Immunol. 2009; 9: 581-593Crossref PubMed Scopus (2872) Google Scholar) of a number of molecules serves to coordinate and fine-tune the local inflammatory response according to the particular circumstances. Here we present evidence that CD157 is one of these molecules. We used antibody-mediated cross-linking of CD157 to mimic its natural clustering (a strategy commonly adopted for initiating signal transduction, although the actual mechanism of how this works remains unclear) and demonstrated that CD157 cross-linking promotes β1 and β2 integrin relocation and orchestrates the assembly of signaling-competent membrane domains. The outcome is regulation of monocyte behavior. This unique role of CD157 accounts for its involvement in critical functions of monocytes, including (i) transendothelial migration and (ii) adhesion to ECM proteins. CD157 operates both in non-inflammatory as well as in inflammatory conditions. Indeed, the extent of the inhibitory effects of blocking mAb on transmigration across quiescent and activated endothelium is comparable. However, forced clustering of CD157 through the addition of a secondary cross-linking antibody at the beginning of or during the process is sufficient to significantly restore transmigration, suggesting that CD157 cross-linking triggers signal transduction. The results obtained in adhesion assays strengthened this assumption. Indeed, clustering of CD157 by the addition of a secondary cross-linking antibody to mouse IgG was able to revert the blockade induced by the anti-CD157 mAb. The originally described enzymatic functions of CD157 and CD38 (the other member of the NAD glycohydrolase/ADP-ribosyl cyclase gene family) have progressively given way to a burgeoning array of functions in activation signaling (35Liang F. Qi R.Z. Chang C.F. FEBS Lett. 2001; 506: 207-210Crossref PubMed Scopus (18) Google Scholar, 36Muñoz P. Navarro M.D. Pavón E.J. Salmerón J. Malavasi F. Sancho J. Zubiaur M. J. Biol. Chem. 2003; 278: 50791-50802Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar) and lateral associations with multiple partner molecules on the plasma membrane (36Muñoz P. Navarro M.D. Pavón E.J. Salmerón J. Malavasi F. Sancho J. Zubiaur M. J. Biol. Chem. 2003; 278: 50791-50802Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 37Funaro A. De Monte L.B. Dianzani U. Forni M. Malavasi F. Eur. J. Immunol. 1993; 23: 2407-2411Crossref PubMed Scopus (111) Google Scholar, 38Deaglio S. Zubiaur M. Gregorini A. Bottarel F. Ausiello C.M. Dianzani U. Sancho J. Malavasi F. Blood. 2002; 99: 2490-2498Crossref PubMed Scopus (92) Google Scholar).We demonstrated that antibody-induced CD157 aggregation can elicit rapid intracellular Ca2+ mobilization and promote neutrophil polarization. The efficiency of these effects is proportional to the extent of cross-linking, suggesting that the aggregation of many molecules is crucial to the formation of competent signaling microdomains (11Funaro A. Ortolan E. Ferranti B. Gargiulo L. Notaro R. Luzzatto L. Malavasi F. Blood. 2004; 104: 4269-4278Crossref PubMed Scopus (63) Google Scholar). In alignment with this observation, here we demonstrated that anti-CD157 mAb, which can cross-link two molecules, is not sufficient to drag integrins into rafts and, consequently, to transduce activation signals; hence, it blocks transmigration and adhesion, likely preventing leukocyte interaction with a so far unidentified physiological ligand(s). Further work will be required to unravel the actual molecular mechanism by which the antibody blockade of CD157 interferes with monocyte transmigration and adhesion to ECM proteins.CD157 is bound to the cell membrane by a GPI anchor. This means that it has no access to the cytoplasmic face of the plasma membrane and therefore lacks direct contact with intracellular signaling intermediates. Although the mechanisms underlying signal transduction through GPI-anchored proteins are not fully understood, an accepted model is that these molecules create complexes with membrane-spanning proteins, which then act as a signal transduction device. Here we demonstrated that in human monocytes, CD157 forms a multimolecular complex with integrins. Indeed, according to the co-immunoprecipitation experiments, it is physically bound to CD18 and CD29; furthermore, it functionally interacts with both integrins, as highlighted by adhesion assays.GPI-anchored proteins are generally concentrated in lipid rafts, which are microdomains within the plasma membrane enriched with glycosphingolipids, cholesterol, and several signaling elements (39Simons K. Toomre D. Nat. Rev. Mol. Cell Biol. 2000; 1: 31-39Crossref PubMed Scopus (5110) Google Scholar). Lipid rafts are thought to provide the milieu necessary for bringing discrete receptors and downstream intermediates into close proximity, thereby allowing the formation of signaling-competent microdomains. Our data showed that (i) CD157 is virtually entirely located within the lipid rafts on the THP-1 cell membrane and (ii) CD157 clustering causes CD18 and CD29 integrins to accumulate in the lipid rafts, much in the same way as with selected ECM proteins (40Cherukuri A. Dykstra M. Pierce S.K. Immunity. 2001; 14: 657-660Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar).Activated β1 and β2 integrins, but not inactive molecules, were reported as preferentially localized in lipid rafts in lymphocytes (41Leitinger B. Hogg N. J. Cell Sci. 2002; 115: 963-972Crossref PubMed Google Scholar). The recruitment of integrins into lipid rafts was postulated as being a mechanism regulating their activity (42Marwali M.R. Rey-Ladino J. Dreolini L. Shaw D. Takei F. Blood. 2003; 102: 215-222Crossref PubMed Scopus (99) Google Scholar). The affinity for lipid rafts is an inherent feature of integrins as it is shared by integrins activated in several ways (43van Zanten T.S. Cambi A. Koopman M. Joosten B. Figdor C.G. Garcia-Parajo M.F. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 18557-18562Crossref PubMed Scopus (177) Google Scholar). Conceivably, in addition to the interaction with their ligand, integrins could be held within the lipid rafts as a result of their lateral association with membrane proteins residing within them (44Porter J.C. Hogg N. Trends Cell Biol. 1998; 8: 390-396Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 45Streuli C.H. Akhtar N. Biochem. J. 2009; 418: 491-506Crossref PubMed Scopus (238) Google Scholar). Our results demonstrate that this is the case for CD157 on monocytes. Indeed, following CD157 aggregation, a considerable amount of both CD18 and CD29 moves to the lipid raft compartment of the cell membrane, resulting in subsequent activation of downstream signaling. The ability to form large raft patches with signaling activity following cross-linking is a feature shared by GPI-anchored molecules (46Harder T. Simons K. Eur. J. Immunol. 1999; 29: 556-562Crossref PubMed Scopus (305) Google Scholar); instead, the promotion of integrin compartmentalization into lipid rafts is not a prerogative of all GPI-anchored molecules. For example, CD87 cross-linking on myeloid cells is unable to promote β2 integrin redistribution into lipid rafts (47Sitrin R.G. Johnson D.R. Pan P.M. Harsh D.M. Huang J. Petty H.R. Blackwood R.A. Am. J. Respir. Cell Mol. Biol. 2004; 30: 233-241Crossref PubMed Scopus (41) Google Scholar). The existence of physical interactions between CD157 and integrins provides a compelling basis for motivating their functional interplay; however, the molecular bases supporting the structural interaction of CD157 with different integrins remain unclear and deserve further investigation. These findings indicate that CD157 (i) behaves as a molecular organizer of membrane microdomains and (ii) is part of the integrin-driven molecular machinery that regulates crucial functions of monocytes, including transendothelial migration and adhesion to ECM proteins.To explore the signal transduction cascade raised by CD157 engagement, we assessed the phosphorylation status of selected proteins upon CD157 antibody cross-linking and demonstrated that CD157-mediated intracellular signaling relies on integrin/Src/FAK, leading to increased activity of downstream MAPK/ERK1/2 and PI3K/Akt pathways. These pathways are core components of the integrin-mediated signaling network coordinating complex biological responses of monocytes, such as cell growth, adhesion, and migration, in normal and pathological conditions (48Abram C.L. Lowell C.A. Annu. Rev. Immunol. 2009; 27: 339-362Crossref PubMed Scopus (384) Google Scholar).In this dynamic interplay between CD157 and integrins, not only does CD157 share effector targets with β1 and β2 integrins, which represent crucial checkpoints of leukocyte trafficking, but it also acts as a stimulatory molecule and cooperates with both integrins in the control of cell migration and adhesion. Indeed, concurrent engagement of CD157 and integrins resulted in increased tyrosine kinase receptor phosphorylation and PI3K and MAPK signaling cascade activation. This is consistent with previous reports demonstrating the need to aggregate integrins on monocyte plasma membrane to achieve maximal tyrosine phosphorylation leading to optimal effector functions (49Miyamoto S. Akiyama S.K. Yamada K.M. Science. 1995; 267: 883-885Crossref PubMed Scopus (788) Google Scholar, 50Cambi A. Joosten B. Koopman M. de Lange F. Beeren I. Torensma R. Fransen J.A. Garcia-Parajó M. van Leeuwen F.N. Figdor C.G. Mol. Biol. Cell. 2006; 17: 4270-4281Crossref PubMed Scopus (101) Google Scholar).It is easy to imagine that in a physiological context, CD157 engagement by its non-substrate ligand (so far unknown) recruits pre-existing β1 and β2 integrin nanoclusters (50Cambi A. Joosten B. Koopman M. de Lange F. Beeren I. Torensma R. Fransen J.A. Garcia-Parajó M. van Leeuwen F.N. Figdor C.G. Mol. Biol. Cell. 2006; 17: 4270-4281Crossref PubMed Scopus (101) Google Scholar) into lipid rafts, thus influencing their three-dimensional organization and promoting the transduction of intracellular signals, which drive efficient cytoskeletal rearrangements, cell adhesion, and transmigration. These conclusions are further supported by the observation that neutrophils from patients with paroxysmal nocturnal hemoglobinuria (which express neither CD157 nor other GPI-anchored molecules as a result of an acquired genetic mutation) (51Luzzatto L. Curr. Opin. Genet. Dev. 2006; 16: 317-322Crossref PubMed Scopus (41) Google Scholar) are characterized by defective transendothelial migration and adhesion to ECM proteins (11Funaro A. Ortolan E. Ferranti B. Gargiulo L. Notaro R. Luzzatto L. Malavasi F. Blood. 2004; 104: 4269-4278Crossref PubMed Scopus (63) Google Scholar, 14Ortolan E. Tibaldi E.V. Ferranti B. Lavagno L. Garbarino G. Notaro R. Luzzatto L. Malavasi F. Funaro A. Blood. 2006; 108: 4214-4222Crossref PubMed Scopus (38) Google Scholar).It is tempting to speculate that the spatial reorganization induced in vitro by mAb cross-linking is a general mechanism implemented in vivo by the interaction between CD157 and its ligand to offer cells (leukocytes or ovarian tumor cells (9Ortolan E. Arisio R. Morone S. Bovino P. Lo-Buono N. Nacci G. Parrotta R. Katsaros D. Rapa I. Migliaretti G. Ferrero E. Volante M. Funaro A. J. Natl. Cancer Inst. 2010; 102: 1160-1177Crossref PubMed Scopus (45) Google Scholar)) with privileged areas for optimal response to the outside environment. The identification of a non-substrate ligand of CD157 is expected to shed light on these issues. 6A. Funaro, manuscript in preparation. In conclusion, these results begin to outline a model where CD157 controls leukocyte extravasation through relocation of integrins into signaling-competent microdomains (i.e. signalosomes), which are required to efficiently recruit protein tyrosine kinases and scaffolding proteins and to switch on the complex network of interconnected signaling pathways (21Ley K. Laudanna C. Cybulsky M.I. Nourshargh S. Nat. Rev. Immunol. 2007; 7: 678-689Crossref PubMed Scopus (3015) Google Scholar, 52Rose D.M. Alon R. Ginsberg M.H. Immunol. Rev. 2007; 218: 126-134Crossref PubMed Scopus (182) Google Scholar).Integrins are attractive targets for the treatment of inflammatory and autoimmune diseases, and several specific antibodies have been tested in clinical trials. However, the integrin-blocking approaches have significant side effects related to impaired host response (53Clifford D.B. De Luca A. Simpson D.M. Arendt G. Giovannoni G. Nath A. Lancet Neurol. 2010; 9: 438-446Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar). The existence of CD157 as an integrin-associated molecule that mediates specific functions offers the potential for fine-tuning integrin functions and permitting the development of improved therapeutic strategies in inflammatory diseases such as arthritis and atherosclerosis. IntroductionEctoenzymes include a heterogeneous group of surface molecules with multiple functions. In addition to interacting with specific substrates, many of them participate in leukocyte activation and migration. In some cases, ectoenzymes exert enzymatic control of leukocyte trafficking (1Salmi M. Jalkanen S. Nat. Rev. Immunol. 2005; 5: 760-771Crossref PubMed Scopus (221) Google Scholar). Other functions are independent of their enzymatic ability, relying on the activation of signaling cascades that lead to calcium fluxes, cytoskeletal remodeling, and release of inflammatory mediators (2Airas L. Niemelä J. Jalkanen S. J. Immunol. 2000; 165: 5411-5417Crossref PubMed Scopus (66) Google Scholar, 3Mina-Osorio P. Winnicka B. O'Conor C. Grant C.L. Vogel L.K. Rodriguez-Pinto D. Holmes K.V. Ortega E. Shapiro L.H. J. Leukoc. Biol. 2008; 84: 448-459Crossref PubMed Scopus (53) Google Scholar). In selected cases, ectoenzymes associate with adhesion molecules to regulate their signaling (4Ossowski L. Aguirre-Ghiso J.A. Curr. Opin. Cell Biol. 2000; 12: 613-620Crossref PubMed Scopus (355) Google Scholar, 5Frasca L. Fedele G. Deaglio S. Capuano C. Palazzo R. Vaisitti T. Malavasi F. Ausiello C.M. Blood. 2006; 107: 2392-2399Crossref PubMed Scopus (101) Google Scholar).Along with CD38, human CD157 constitutes the NAD glycohydrolase/ADP-ribosyl cyclase gene family (6Ferrero E. Malavasi F. J. Leukoc. Biol. 1999; 65: 151-161Crossref PubMed Scopus (66) Google Scholar). These two molecules share 36% of their protein sequence, including 10 cysteine residues forming intrachain disulfide bonds. However, they differ in structure, with CD157 being a glycosylphosphatidylinositol (GPI) 5The abbreviations used are: GPI, glycosylphosphatidylinositol; F(ab′)2 RαMIgG, F(ab′)2 fraction of rabbit antibodies to mouse IgG; mIgG, mouse monoclonal IgG; FN, fibronectin; Ctx, cholera toxin β-subunit; MCP-1, monocyte chemoattractant protein-1; HPMEC, human pulmonary microvascular endothelial cell line; ECM, extracellular matrix protein; FAK, focal adhesion kinase; TMI, transmigration index. -anchored glycoprotein and CD38 being a transmembrane type II glycoprotein (7Malavasi F. Deaglio S. Funaro A. Ferrero E. Horenstein A.L. Ortolan E. Vaisitti T. Aydin S. Physiol. Rev. 2008; 88: 841-886Crossref PubMed Scopus (588) Google Scholar). CD157 is mainly expressed by cells of the myeloid lineage, bone marrow stroma, and vascular endothelium (8Ortolan E. Vacca P. Capobianco A. Armando E. Crivellin F. Horenstein A. Malavasi F. Cell Biochem. Funct. 2002; 20: 309-322Crossref PubMed Scopus (48) Google Scholar). CD157 is also expressed by ovarian cancer epithelium and by peritoneal mesothelial cells, where it is implicated in tumor dissemination (9Ortolan E. Arisio R. Morone S. Bovino P. Lo-Buono N. Nacci G. Parrotta R. Katsaros D. Rapa I. Migliaretti G. Ferrero E. Volante M. Funaro A. J. Natl. Cancer Inst. 2010; 102: 1160-1177Crossref PubMed Scopus (45) Google Scholar). Further, it is endowed with receptor-like features observed in different cell types (10Ishihara K. Hirano T. Chem. Immunol. 2000; 75: 235-255Crossref PubMed Google Scholar) and transduces signals by interacting with transmembrane partner molecules (11Funaro A. Ortolan E. Ferranti B. Gargiulo L. Notaro R. Luzzatto L. Malavasi F. Blood. 2004; 104: 4269-4278Crossref PubMed Scopus (63) Google Scholar, 12Lavagno L. Ferrero E. Ortolan E. Malavasi F. Funaro A. J. Biol. Regul. Homeost. Agents. 2007; 21: 5-11PubMed Google Scholar), a strategy shared by other GPI-anchored molecules (13Todd 3rd, R.F. Petty H.R. J. Lab. Clin. Med. 1997; 129: 492-498Abstract Full Text PDF PubMed Scopus (93) Google Scholar).CD157 is involved in neutrophil polarization, adhesion, and motility (11Funaro A. Ortolan E. Ferranti B. Gargiulo L. Notaro R. Luzzatto L. Malavasi F. Blood. 2004; 104: 4269-4278Crossref PubMed Scopus (63) Google Scholar) and controls transendothelial migration (14Ortolan E. Tibaldi E.V. Ferranti B. Lavagno L. Garbarino G. Notaro R. Luzzatto L. Malavasi F. Funaro A. Blood. 2006; 108: 4214-4222Crossref PubMed Scopus (38) Google Scholar). This study extends the analysis of the functional role of CD157 to human monocytes, adopted as a physiological model in which to explore the molecular mechanism underlying the role of the molecule in the control of cell motility.Monocytes play key functions in innate and adaptive immunity, immune surveillance, host defense, and inflammation (15Yona S. Jung S. Curr. Opin. Hematol. 2010; 17: 53-59Crossref PubMed Scopus (184) Google Scholar). Furthermore, monocyte trafficking is a critical factor in inflammatory and autoimmune diseases, such as atherosclerosis, multiple sclerosis, and rheumatoid arthritis (16Ross R. N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (19071) Google Scholar).Monocytes originate from hematopoietic precursors in the bone marrow and circulate in the blood for 24–48 h before extravasating into the connective tissues. In inflammation, monocytes are recruited to the affected tissues, where they differentiate into macrophages and dendritic cells (17Kamei M. Carman C.V. Curr. Opin. Hematol. 2010; 17: 43-52Crossref PubMed Scopus (65) Google Scholar). The continuous traffic from blood to tissue and from tissue to lymph nodes relies on orchestrated sequential interactions between leukocytes and vascular or lymphatic endothelium (18Springer T.A. Cell. 1994; 76: 301-314Abstract Full Text PDF PubMed Scopus (6373) Google Scholar). Each step is a prerequisite for the next one. Cell adhesion molecules (such as selectins and integrins) have well established roles in supporting tethering, rolling, and firm adhesion to the vascular endothelium (19Luster A.D. Alon R. von Andrian U.H. Nat. Immunol. 2005; 6: 1182-1190Crossref PubMed Scopus (917) Google Scholar). Chemokines and selected molecules at the endothelial junctions (including CD31, JAM-1, vascular endothelial cadherin, and CD99) are critical in the control of the transmigration process (20Vestweber D. Immunol. Rev. 2007; 218: 178-196Crossref PubMed Scopus (237) Google Scholar). These central components are flanked by an increasing number of molecules from different families, which contribute to distinct steps of the extravasation cascade (21Ley K. Laudanna C. Cybulsky M.I. Nourshargh S. Nat. Rev. Immunol. 2007; 7: 678-689Crossref PubMed Scopus (3015) Google Scholar).The results obtained in this study indicate that CD157 is involved in the control of monocyte extravasation and adhesion to ECM proteins. CD157 establishes a structural interaction with β1 and β2 integrin and, following antibody-induced cross-linking, it promotes their relocation into detergent-resistant domains, thus driving the dynamic reorganization of signaling-competent membrane microdomains. Moreover, CD157 effectively contributes to the integrin-driven signaling network that is critical during monocyte transmigration.
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