AM3 modulates dendritic cell pathogen recognition capabilities by targeting DC-SIGN
Diego Serrano-Gómez, Rocío T Martínez-Nuñez, Elena Sierra-Filardi, Nuria Izquierdo, María Colmenares, Jesús Pla, Luis Rivas, Javier Martinez-Picado, Jesús Jimenez-Barbero, José Luis Alonso-Lebrero, Salvador González, Angel L Corbí, Diego Serrano-Gómez, Rocío T Martínez-Nuñez, Elena Sierra-Filardi, Nuria Izquierdo, María Colmenares, Jesús Pla, Luis Rivas, Javier Martinez-Picado, Jesús Jimenez-Barbero, José Luis Alonso-Lebrero, Salvador González, Angel L Corbí
Abstract
AM3 (Inmunoferon) is an orally effective immunomodulator that influences the regulatory and effector functions of the immune system whose molecular mechanisms of action are mostly unknown. We hypothesized that the polysaccharide moiety of AM3 (IF-S) might affect immune responses by modulating the lectin-dependent pathogen recognition abilities of human dendritic cells. IF-S inhibited binding of viral, fungal, and parasite pathogens by human monocyte-derived dendritic cells in a dose-dependent manner. IF-S specifically impaired the pathogen recognition capabilities of DC-SIGN, as it reduced the attachment of Candida, Aspergillus, and Leishmania to DC-SIGN transfectants. IF-S also inhibited the interaction of DC-SIGN with both its cellular counterreceptor (intercellular adhesion molecule 3) and the human immunodeficiency virus (HIV) type 1 gp120 protein and blocked the DC-SIGN-dependent capture of HIV virions and the HIV trans-infection capability of DC-SIGN transfectants. IF-S promoted DC-SIGN internalization in DCs without affecting mannose receptor expression, and (1)D saturation transfer difference nuclear magnetic resonance demonstrated that IF-S directly interacts with DC-SIGN on the cell surface. Therefore, the polysaccharide moiety of AM3 directly influences pathogen recognition by dendritic cells by interacting with DC-SIGN. Our results indicate that DC-SIGN is the target for an immunomodulator and imply that the adjuvant and immunomodulatory actions of AM3 are mediated, at least in part, by alteration of the DC-SIGN functional activities.
Figures
References
- Alvarez, C. P., F. Lasala, J. Carrillo, O. Muniz, A. L. Corbi, and R. Delgado. 2002. C-type lectins DC-SIGN and L-SIGN mediate cellular entry by Ebola virus in cis and in trans. J. Virol. 766841-6844.
- Alvarez-Mon, M., M. Miravitlles, J. Morera, L. Callol, and J. L. Alvarez-Sala. 2005. Treatment with the immunomodulator AM3 improves the health-related quality of life of patients with COPD. Chest 1271212-1218.
- Banchereau, J., and R. M. Steinman. 1998. Dendritic cells and the control of immunity. Nature 392245-252.
- Blake, J. S., M. V. Dahl, M. J. Herron, and R. D. Nelson. 1991. An immunoinhibitory cell wall glycoprotein (mannan) from Trichophyton rubrum. J. Investig. Dermatol. 96657-661.
- Brieva, A., A. Guerrero, J. L. Alonso-Lebrero, and J. P. Pivel. 2001. Immunoferon, a glycoconjugate of natural origin, inhibits LPS-induced TNF-alpha production and inflammatory responses. Int. Immunopharmacol. 11979-1987.
- Brieva, A., A. Guerrero, and J. P. Pivel. 2002. Inmunoferon, a glycoconjugate of natural origin, regulates the liver response to inflammation and inhibits TNF-alpha production by an HPA axis-dependent mechanism. Int. Immunopharmacol. 2807-813.
- Cambi, A., K. Gijzen, J. M. de Vries, R. Torensma, B. Joosten, G. J. Adema, M. G. Netea, B. J. Kullberg, L. Romani, and C. G. Figdor. 2003. The C-type lectin DC-SIGN (CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells. Eur. J. Immunol. 33532-538.
- Caparros, E., P. Munoz, E. Sierra-Filardi, D. Serrano-Gomez, A. Puig-Kroger, J. L. Rodriguez-Fernandez, M. Mellado, J. Sancho, M. Zubiaur, and A. L. Corbi. 2006. DC-SIGN ligation on dendritic cells results in ERK and PI3K activation and modulates cytokine production. Blood 1073950-3958.
- Chehimi, J., Q. Luo, L. Azzoni, L. Shawver, N. Ngoubilly, R. June, G. Jerandi, M. Farabaugh, and L. J. Montaner. 2003. HIV-1 transmission and cytokine-induced expression of DC-SIGN in human monocyte-derived macrophages. J. Leukoc. Biol. 74757-763.
- Claasen, B., M. Axmann, R. Meinecke, and B. Meyer. 2005. Direct observation of ligand binding to membrane proteins in living cells by a saturation transfer double difference (STDD) NMR spectroscopy method shows a significantly higher affinity of integrin alpha(IIb)beta3 in native platelets than in liposomes. J. Am. Chem. Soc. 127916-919.
- Colmenares, M., A. L. Corbi, S. J. Turco, and L. Rivas. 2004. The dendritic cell receptor DC-SIGN discriminates among species and life cycle forms of Leishmania. J. Immunol. 1721186-1190.
- Colmenares, M., A. Puig-Kroger, O. M. Pello, A. L. Corbi, and L. Rivas. 2002. Dendritic cell (DC)-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN, CD209), a C-type surface lectin in human DCs, is a receptor for Leishmania amastigotes. J. Biol. Chem. 27736766-36769.
- Curtis, B. M., S. Scharnowske, and A. J. Watson. 1992. Sequence and expression of a membrane-associated C-type lectin that exhibits CD4-independent binding of human immunodeficiency virus envelope glycoprotein gp120. Proc. Natl. Acad. Sci. USA. 898356-8360.
- de la Rosa, G., M. Yanez-Mo, R. Samaneigo, D. Serrano-Gomez, L. Martinez-Munoz, E. Fernandez-Ruiz, N. Longo, F. Sanchez-Madrid, A. L. Corbi, and P. Sanchez-Mateos. 2005. Regulated recruitment of DC-SIGN to cell-cell contact regions during zymosan-induced human dendritic cell aggregation. J. Leukoc. Biol. 77699-709.
- Engering, A., T. B. Geijtenbeek, S. J. van Vliet, M. Wijers, E. van Liempt, N. Demaurex, A. Lanzavecchia, J. Fransen, C. G. Figdor, V. Piguet, and Y. van Kooyk. 2002. The dendritic cell-specific adhesion receptor DC-SIGN internalizes antigen for presentation to T cells. J. Immunol. 1682118-2126.
- Engering, A., S. J. Van Vliet, T. B. Geijtenbeek, and Y. Van Kooyk. 2002. Subset of DC-SIGN(+) dendritic cells in human blood transmits HIV-1 to T lymphocytes. Blood 1001780-1786.
- Feinberg, H., D. A. Mitchell, K. Drickamer, and W. I. Weis. 2001. Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR. Science 2942163-2166.
- Frison, N., M. E. Taylor, E. Soilleux, M. T. Bousser, R. Mayer, M. Monsigny, K. Drickamer, and A. C. Roche. 2003. Oligolysine-based oligosaccharide clusters: selective recognition and endocytosis by the mannose receptor and dendritic cell-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin. J. Biol. Chem. 27823922-23929.
- Geijtenbeek, T. B., D. J. Krooshoop, D. A. Bleijs, S. J. van Vliet, G. C. van Duijnhoven, V. Grabovsky, R. Alon, C. G. Figdor, and Y. van Kooyk. 2000. DC-SIGN-ICAM-2 interaction mediates dendritic cell trafficking. Nat. Immunol. 1353-357.
- Geijtenbeek, T. B., D. S. Kwon, R. Torensma, S. J. van Vliet, G. C. van Duijnhoven, J. Middel, I. L. Cornelissen, H. S. Nottet, V. N. KewalRamani, D. R. Littman, C. G. Figdor, and Y. van Kooyk. 2000. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100587-597.
- Geijtenbeek, T. B., R. Torensma, S. J. van Vliet, G. C. van Duijnhoven, G. J. Adema, Y. van Kooyk, and C. G. Figdor. 2000. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100575-585.
- Geijtenbeek, T. B., S. J. Van Vliet, E. A. Koppel, M. Sanchez-Hernandez, C. M. Vandenbroucke-Grauls, B. Appelmelk, and Y. Van Kooyk. 2003. Mycobacteria target DC-SIGN to suppress dendritic cell function. J. Exp. Med. 1977-17.
- Geijtenbeek, T. B., S. J. van Vliet, G. C. van Duijnhoven, C. G. Figdor, and Y. van Kooyk. 2001. DC-SIGN, a dentritic cell-specific HIV-1 receptor present in placenta that infects T cells in trans—a review. Placenta 22(Suppl. A)S19-S23.
- Lozach, P. Y., H. Lortat-Jacob, A. de Lacroix de Lavalette, I. Staropoli, S. Foung, A. Amara, C. Houles, F. Fieschi, O. Schwartz, J. L. Virelizier, F. Arenzana-Seisdedos, and R. Altmeyer. 2003. DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2. J. Biol. Chem. 27820358-20366.
- Majano, P., J. L. Alonso-Lebrero, A. Janczyk, S. Martin-Vichez, F. Molina-Jimenez, A. Brieva, J. P. Pivel, S. Gonzalez, M. Lopez-Cabrera, and R. Moreno-Otero. 2005. AM3 inhibits LPS-induced iNOS expression in mice. Int. Immunopharmacol. 51165-1170.
- Mari, S., D. Serrano-Gomez, F. J. Canada, A. L. Corbi, and J. Jimenez-Barbero. 2004. 1D saturation transfer difference NMR experiments on living cells: the DC-SIGN/oligomannose interaction. Angew. Chem. Int. Ed. Engl. 44296-298.
- Mayer, M., and B. Meyer. 2001. Group epitope mapping by saturation transfer difference NMR to identify segments of a ligand in direct contact with a protein receptor. J. Am. Chem. Soc. 1236108-6117.
- Meyer, B., and T. Peters. 2003. NMR spectroscopy techniques for screening and identifying ligand binding to protein receptors. Angew. Chem. Int. Ed. Engl. 42864-890.
- Meyer, S., E. van Liempt, A. Imberty, Y. van Kooyk, H. Geyer, R. Geyer, and I. van Die. 2005. DC-SIGN mediates binding of dendritic cells to authentic pseudo-LewisY glycolipids of Schistosoma mansoni cercariae, the first parasite-specific ligand of DC-SIGN. J. Biol. Chem. 28037349-37359.
- Meyer-Wentrup, F., A. Cambi, G. J. Adema, and C. G. Figdor. 2005. “Sweet talk”: closing in on C type lectin signaling. Immunity 22399-400.
- Nigou, J., M. Gilleron, M. Rojas, L. F. Garcia, M. Thurnher, and G. Puzo. 2002. Mycobacterial lipoarabinomannans: modulators of dendritic cell function and the apoptotic response. Microbes Infect. 4945-953.
- Perez-Garcia, R., A. Perez-Garcia, D. Verbeelen, E. D. Bernstein, V. G. Villarrubia, and M. Alvarez-Mon. 2002. AM3 (Inmunoferon) as an adjuvant to hepatitis B vaccination in hemodialysis patients. Kidney Int. 611845-1852.
- Pohlmann, S., J. Zhang, F. Baribaud, Z. Chen, G. J. Leslie, G. Lin, A. Granelli-Piperno, R. W. Doms, C. M. Rice, and J. A. McKeating. 2003. Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR. J. Virol. 774070-4080.
- Prieto, A., E. Reyes, E. D. Bernstein, B. Martinez, J. Monserrat, J. L. Izquierdo, L. Callol, P. de Lucas, R. Alvarez-Sala, J. L. Alvarez-Sala, V. G. Villarrubia, and M. Alvarez-Mon. 2001. Defective natural killer and phagocytic activities in chronic obstructive pulmonary disease are restored by glycophosphopeptical (Inmunoferon). Am. J. Respir. Crit. Care Med. 1631578-1583.
- Ramamoorthy, L., M. C. Kemp, and I. R. Tizard. 1996. Acemannan, a beta-(1,4)-acetylated mannan, induces nitric oxide production in macrophage cell line RAW 264.7. Mol. Pharmacol. 50878-884.
- Rogers, N. C., E. C. Slack, A. D. Edwards, M. A. Nolte, O. Schulz, E. Schweighoffer, D. L. Williams, S. Gordon, V. L. Tybulewicz, G. D. Brown, and E. S. C. Reis. 2005. Syk-dependent cytokine induction by dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22507-517.
- Rojo, J. M., M. T. Rejas, G. Ojeda, P. Portoles, and I. Barasoain. 1986. Enhancement of lymphocyte proliferation, interleukin-2 production and NK activity by Inmunoferon (AM-3), a fungal immunomodulator: variations in normal and immunosuppressed mice. Int. J. Immunopharmacol. 8593-597.
- Sanchez, L., E. Pena, A. Civantos, G. Sada, M. M. Alvarez, M. A. Chirigos, and V. G. Villarrubia. 1995. AM3, an adjuvant to hepatitis B revaccination in non-responder healthy persons. J. Hepatol. 22119-121.
- Schjetne, K. W., K. M. Thompson, T. Aarvak, B. Fleckenstein, L. M. Sollid, and B. Bogen. 2002. A mouse C kappa-specific T cell clone indicates that DC-SIGN is an efficient target for antibody-mediated delivery of T cell epitopes for MHC class II presentation. Int. Immunol. 141423-1430.
- Serrano-Gomez, D., A. Dominguez-Soto, J. Ancochea, J. A. Jimenez-Heffernan, J. A. Leal, and A. L. Corbi. 2004. Dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin mediates binding and internalization of Aspergillus fumigatus conidia by dendritic cells and macrophages. J. Immunol. 1735635-5643.
- Steinman, R. M., D. Hawiger, and M. C. Nussenzweig. 2003. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21685-711.
- Tacken, P. J., I. J. de Vries, K. Gijzen, B. Joosten, D. Wu, R. P. Rother, S. J. Faas, C. J. Punt, R. Torensma, G. J. Adema, and C. G. Figdor. 2005. Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti-DC-SIGN antibody. Blood 1061278-1285.
- Tailleux, L., O. Schwartz, J. L. Herrmann, E. Pivert, M. Jackson, A. Amara, L. Legres, D. Dreher, L. P. Nicod, J. C. Gluckman, P. H. Lagrange, B. Gicquel, and O. Neyrolles. 2003. DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. J. Exp. Med. 197121-127.
- Takeda, K., T. Kaisho, and S. Akira. 2003. Toll-like receptors. Annu. Rev. Immunol. 21335-376.
- Tassaneetrithep, B., T. H. Burgess, A. Granelli-Piperno, C. Trumpfheller, J. Finke, W. Sun, M. A. Eller, K. Pattanapanyasat, S. Sarasombath, D. L. Birx, R. M. Steinman, S. Schlesinger, and M. A. Marovich. 2003. DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. J. Exp. Med. 197823-829.
- van Gisbergen, K. P., M. Sanchez-Hernandez, T. B. Geijtenbeek, and Y. van Kooyk. 2005. Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between Mac-1 and DC-SIGN. J. Exp. Med. 2011281-1292.
- van Kooyk, Y., A. Engering, A. N. Lekkerkerker, I. S. Ludwig, and T. B. Geijtenbeek. 2004. Pathogens use carbohydrates to escape immunity induced by dendritic cells. Curr. Opin. Immunol. 16488-493.
- van Kooyk, Y., and T. B. Geijtenbeek. 2003. DC-SIGN: escape mechanism for pathogens. Nat. Rev. Immunol. 3697-709.
- Varela, J., M. L. Navarro Pico, A. Guerrero, F. Garcia, G. Gimenez Gallego, and J. P. Pivel. 2002. Identification and characterization of the peptidic component of the immunomodulatory glycoconjugate Immunoferon. Methods Find. Exp. Clin. Pharmacol. 24471-480.
- Yoshitomi, H., N. Sakaguchi, K. Kobayashi, G. D. Brown, T. Tagami, T. Sakihama, K. Hirota, S. Tanaka, T. Nomura, I. Miki, S. Gordon, S. Akira, T. Nakamura, and S. Sakaguchi. 2005. A role for fungal β-glucans and their receptor dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J. Exp. Med. 201949-960.
Source: PubMed