Abstract
Studies of osteopontin (OPN)-dependent regulation of immune responses have focused on the cytokine activities of the secreted form of this protein. Recent evidence has revealed that an intracellular form of OPN expressed by dendritic cells regulates the expression of pro-inflammatory cytokines and the differentiation of T helper (TH)-cell lineages. In this Opinion article, we discuss the properties of both OPN isoforms and their respective contributions to the immune response. We propose that cell-type-specific expression of secreted and intracellular OPN regulates the development of distinct effector TH cells, including that of TH1 and TH17 cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ashkar, S. et al. Eta-1 (osteopontin): an early component of type 1 (cell-mediated) immunity. Science 287, 860–864 (2000).
Shinohara, M. L. et al. T-bet-dependent expression of osteopontin contributes to T cell polarization. Proc. Natl Acad. Sci USA 102, 17101–17106 (2005).
Weiss, J. M. et al. Osteopontin is involved in the initiation of cutaneous contact hypersensitivity by inducing Langerhans and dendritic cell migration to lymph nodes. J. Exp. Med. 194, 1219–1229 (2001).
Zohar, R. et al. Single cell analysis of intracellular osteopontin in osteogenic cultures of fetal rat calvarial cells. J. Cell Physiol. 170, 88–100 (1997).
Zohar, R. et al. Intracellular osteopontin is an integral component of the CD44–ERM complex involved in cell migration. J. Cell Physiol. 184, 118–130 (2000).
Suzuki, K. et al. Colocalization of intracellular osteopontin with CD44 is associated with migration, cell fusion, and resorption in osteoclasts. J. Bone Miner. Res. 17, 1486–1497 (2002).
Zhu, B. et al. Osteopontin modulates CD44-dependent chemotaxis of peritoneal macrophages through G-protein-coupled receptors: evidence of a role for an intracellular form of osteopontin. J. Cell Physiol. 198, 155–167 (2004).
Shinohara, M. L., Kim, H.-J., Kim, J.-H., Garcia, V. A. & Cantor, H. Alternative translation of osteopontin generates intracellular and secreted isoforms that mediate distinct biological activities in dendritic cells. Proc. Natl Acad. Sci. USA 105, 7235–7239 (2008).
Shinohara, M. L. et al. Osteopontin expression is essential for IFN-α production by plasmacytoid dendritic cells. Nature Immunol. 7, 498–506 (2006).
Maeno, Y. et al. Osteopontin participates in Th1-mediated host resistance against nonlethal malaria parasite Plasmodium chabaudi chabaudi infection in mice. Infect. Immun. 74, 2423–2427 (2006).
Shinohara, M. L., Kim, J.-H., Garcia, V. A. & Cantor, H. Engagement of the type-I interferon receptor on dendritic cells inhibits promotion of Th17 cells: role of intracellular osteopontin. Immunity 29, 68–78 (2008).
Patarca, R. et al. Structural and functional studies of the early T lymphocyte activation 1 (Eta-1) gene. Definition of a novel T cell-dependent response associated with genetic resistance to bacterial infection. J. Exp. Med. 170, 145–161 (1989).
Fet, V., Dickinson, M. E. & Hogan, B. L. Localization of the mouse gene for secreted phosphoprotein 1 (Spp1) (2ar, osteopontin, bone sialoprotein 1, 44kDa bone phosphoprotein, tumor-secreted phosphoprotein) to chromosome 5, closely linked to Ric (Rickettsia resistance). Genomics 5, 375–377 (1989).
Weber, G. F., Ashkar, S., Glimcher, M. J. & Cantor, H. Receptor–ligand interaction between CD44 and osteopontin/Eta-1. Science 271, 509–512 (1996).
Nau, G. J. et al. Attenuated host resistance against Mycobacterium bovis BCG infection in mice lacking osteopontin. Infect. Immun. 67, 4223–4230 (1999).
Nau, G. J. et al. Osteopontin expression correlates with clinical outcome in patients with mycobacterial infection. Am. J. Pathol. 157, 37–42 (2000).
Koguchi, Y. et al. High plasma osteopontin level and its relationship with interleukin-12-mediated type 1 helper cell response in tuberculosis. Am. J. Respir. Crit. Care Med. 167, 1355–1359 (2003).
Kadota, J. et al. High plasma concentrations of osteopontin in patients with interstitial pneumonia. Respir. Med. 99, 111–117 (2005).
Rollo, E. E. et al. The cytokine osteopontin modulates the severity of rotavirus diarrhea. J. Virol. 79, 3509–3516 (2005).
Erb, K. J., Kirman, J., Delahunt, B., Chen, W. & Le Gros, G. IL-4, IL-5 and IL-10 are not required for the control of M. bovis-BCG infection in mice. Immunol. Cell Biol. 76, 41–46 (1998).
Abel, B., Freigang, S., Bachmann, M. F., Boschert, U. & Kopf, M. Osteopontin is not required for the development of Th1 responses and viral immunity. J. Immunol. 175, 6006–6013 (2005).
Craig-Mylius, K., Weber, G. F., Coburn, J. & Glickstein, L. Borrelia burgdorferi, an extracellular pathogen, circumvents osteopontin in inducing an inflammatory cytokine response. J. Leukoc. Biol. 77, 710–718 (2005).
Barchet, W. et al. Dendritic cells respond to influenza virus through TLR7- and PKR-independent pathways. Eur. J. Immunol. 35, 236–242 (2005).
Lazarus, J. J., Meadows, M. J., Lintner, R. E. & Wooten, R. M. IL-10 deficiency promotes increased Borrelia burgdorferi clearance predominantly through enhanced innate immune responses. J. Immunol. 177, 7076–7085 (2006).
Patarca, R., Wei, F.-Y., Singh, P., Morasso, M. I. & Cantor, H. Dysregulated expression of the T-cell cytokine Eta-1 in CD4-8- lymphocytes during the development of murine autoimmune disease. J. Exp. Med. 172, 1177–1183 (1990).
Miyazaki, T. et al. Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice. Eur. J. Immunol. 35, 1510–1520 (2005).
Chiocchetti, A. et al. High levels of osteopontin associated with polymorphisms in its gene are a risk factor for development of autoimmunity/lymphoproliferation. Blood 103, 1376–1382 (2004).
Forton, A. C., Petri, M. A., Goldman, D. & Sullivan, K. E. An osteopontin (SPP1) polymorphism is associated with systemic lupus erythematosus. Hum. Mutat. 19, 459 (2002).
D'Alfonso, S. et al. Two single-nucleotide polymorphisms in the 5′ and 3′ ends of the osteopontin gene contribute to susceptibility to systemic lupus erythematosus. Arthritis Rheum. 52, 539–547 (2005).
Yumoto, K. et al. Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice. Proc. Natl Acad. Sci. USA 99, 4556–4561 (2002).
Yamamoto, N. et al. Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis. J. Clin. Invest. 112, 181–188 (2003).
Yamamoto, N. et al. Successful treatment of collagen-induced arthritis in non-human primates by chimeric anti-osteopontin antibody. Int. Immunopharmacol. 7, 1460–1470 (2007).
Ishii, T. et al. Mice with osteopontin deletion remain predisposed to collagen-induced arthritis. Arthritis Rheum. 50, 669–671 (2004).
Jacobs, J. P. et al. Lack of requirement of osteopontin for inflammation, bone erosion, and cartilage damage in the K/BxN model of autoantibody-mediated arthritis. Arthritis Rheum. 50, 2685–2694 (2004).
Xanthou, G. et al. A critical role for osteopontin in T helper type 2 allergic airway disease: regulation of plasmacytoid and conventional dendritic cell subsets. Nature Med. 13, 570–578 (2007).
Shinohara, M. L. & Cantor, H. The bridge between dendritic cells and asthma. Nature Med. 13, 536–538 (2007).
Junaid, A., Moon, M. C., Harding, G. E. & Zahradka, P. Osteopontin localizes to the nucleus of 293 cells and associates with polo-like kinase-1. Am. J. Physiol. Cell Physiol. 292, C919–C926 (2007).
Bellahcene, A., Castronovo, V., Ogbureke, K. U., Fisher, L. W. & Fedarko, N. S. Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer. Nature Rev. Cancer 8, 212–226 (2008).
Prinz, M. et al. Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 28, 675–686 (2008).
Brinkmann, V., Geiger, T., Alkan, S. & Heusser, C. H. Interferon α increases the frequency of interferon γ-producing human CD4+ T cells. J. Exp. Med. 178, 1655–1663 (1993).
Cousens, L. P. et al. Two roads diverged: interferon α/β- and interleukin-12-mediated pathways in promoting T cell interferon γ responses during viral infection. J. Exp. Med. 189, 1315–1327 (1999).
Montoya, M. et al. Type I interferons produced by dendritic cells promote their phenotypic and functional activation. Blood 99, 3263–3271 (2002).
Burchill, M. A. et al. Inhibition of interleukin-17 prevents the development of arthritis in vaccinated mice challenged with Borrelia burgdorferi. Infect. Immun. 71, 3437–3442 (2003).
Leibundgut-Landmann, S. et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nature Immunol. 8, 630–638 (2007).
Chabaud, M., Fossiez, F., Taupin, J. L. & Miossec, P. Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. J. Immunol. 161, 409–414 (1998).
Kotake, S. et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J. Clin. Invest. 103, 1345–1352 (1999).
Matusevicius, D. et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult. Scler. 5, 101–104 (1999).
Wong, C. K., Ho, C. Y., Li, E. K. & Lam, C. W. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus 9, 589–593 (2000).
Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nature Med. 8, 500–508 (2002).
Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).
Batten, M. et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nature Immunol. 7, 929–936 (2006).
Stumhofer, J. S. et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nature Immunol. 7, 937–945 (2006).
Guo, B., Chang, E. Y. & Cheng, G. The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J. Clin. Invest. 118, 1680–1690 (2008).
Chabas, D. et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294, 1731–1735 (2001).
Jansson, M., Panoutsakopoulou, V., Baker, J., Klein, L. & Cantor, H. Attenuated experimental autoimmune encephalomyelitis in Eta-1/osteopontin-deficient mice. J. Immunol. 168, 2096–2099 (2002).
Blom, T., Franzen, A., Heinegard, D. & Holmdahl, R. Comment on “The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease”. Science 299, 1845 (2003).
Hur, E. M. et al. Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells. Nature Immunol. 8, 74–83 (2007).
Paty, D. W. & Li, D. K. Interferon β-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology 43, 662–667 (1993).
Langer, J. A. Interferon at 50: new molecules, new potential, new (and old) questions. Sci. STKE 2007, e53 (2007).
Brideau-Andersen, A. D. et al. Directed evolution of gene-shuffled IFN-α molecules with activity profiles tailored for treatment of chronic viral diseases. Proc. Natl Acad. Sci. USA 104, 8269–8274 (2007).
Axtell, R. C. & Steinman, L. Type 1 interferons cool the inflamed brain. Immunity 28, 600–602 (2008).
Author information
Authors and Affiliations
Corresponding author
Related links
Related links
DATABASES
OMIM
FURTHER INFORMATION
Rights and permissions
About this article
Cite this article
Cantor, H., Shinohara, M. Regulation of T-helper-cell lineage development by osteopontin: the inside story. Nat Rev Immunol 9, 137–141 (2009). https://doi.org/10.1038/nri2460
Issue Date:
DOI: https://doi.org/10.1038/nri2460
This article is cited by
-
Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease
Nature Medicine (2023)
-
The utility of serum osteopontin levels for predicting postoperative complications after colorectal cancer surgery
International Journal of Clinical Oncology (2022)
-
White matter injury but not germinal matrix hemorrhage induces elevated osteopontin expression in human preterm brains
Acta Neuropathologica Communications (2021)
-
Osteopontin and the immune system: another brick in the wall
Cellular & Molecular Immunology (2018)
-
The role of α9β1 integrin and its ligands in the development of autoimmune diseases
Journal of Cell Communication and Signaling (2018)