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Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets

Abstract

Osteopontin (Opn) is important for T helper type 1 (TH1) immunity and autoimmunity. However, the role of this cytokine in TH2-mediated allergic disease as well as its effects on primary versus secondary antigenic encounters remain unclear. Here we demonstrate that OPN is expressed in the lungs of asthmatic individuals and that Opn-s, the secreted form of Opn, exerts opposing effects on mouse TH2 effector responses and subsequent allergic airway disease: pro-inflammatory at primary systemic sensitization, and anti-inflammatory during secondary pulmonary antigenic challenge. These effects of Opn-s are mainly mediated by the regulation of TH2-suppressing plasmacytoid dendritic cells (DCs) during primary sensitization and TH2-promoting conventional DCs during secondary antigenic challenge. Therapeutic administration of recombinant Opn during pulmonary secondary antigenic challenge decreased established TH2 responses and protected mice from allergic disease. These effects on TH2 allergic responses suggest that Opn-s is an important therapeutic target and provide new insight into its role in immunity.

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Figure 1: Expression of Opn in the lung in allergic airway disease.
Figure 2: Opn-s blockade at priming reduces allergic disease.
Figure 3: Opn-s blockade at challenge enhances allergic disease.
Figure 4: Spp1−/− mice exhibit enhanced TH2 responses.
Figure 5: Opn-s blockade affects TH2 responses through DC recruitment.
Figure 6: rOpn is protective during pulmonary challenge.

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Acknowledgements

We thank S. Spyridakis for assistance in flow-cytometry, A. Agapaki for histology preparations and S. Pagakis for assistance with final figure preparation. We thank L. Liaw (Maine Medical Center Research Institute) for permission to use the Spp1-deficient mice. We are grateful to M. Doufexis, I. Scotiniotis, C. Tsatsanis and M. Aggelakopoulou for critical reading of the manuscript, and to C. Davos, K. Karalis and A. Tsouroplis for discussions. This work was supported by the Hellenic Ministries of Health and Education (V.P. and G.X.) and by a grant award from the Hellenic Ministry of Development, General Secretariat of Research and Technology (03ED750; V.P.). C.M.L. is supported by a Senior Fellowship from the Wellcome Trust (#057704). B.N.L. is supported by a Vidi grant from the Dutch Organization for Scientific Research. D.C.M.S. is supported by the Thorax Foundation.

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G.X. designed experiments, performed animal studies and immunohistochemistry, generated figures, analyzed data and wrote the manuscript. T.A. performed animal studies, tissue-culture experiments, generated figures and performed flow cytometry. M.S. assisted with the animal studies and tissue-culture experiments. D.C.M.S. assisted with the animal studies and image analysis. E.E. and M.G. performed bronchoscopies, and provided human lung biopsies and clinical characteristics of the individuals. B.N.L. provided antibodies, assisted with the design of experiments and participated in discussions. C.M.L. assisted with experimental design, writing and critical editing of the manuscript. V.P. provided crucial ideas, designed experiments, analyzed data, supervised the study and wrote the manuscript with G.X.

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Correspondence to Vily Panoutsakopoulou.

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Xanthou, G., Alissafi, T., Semitekolou, M. et al. Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets. Nat Med 13, 570–578 (2007). https://doi.org/10.1038/nm1580

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