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The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss

Nature Immunology volume 13, pages 465–473 (2012)Cite this article

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Abstract

Aging is linked to greater susceptibility to chronic inflammatory diseases, several of which, including periodontitis, involve neutrophil-mediated tissue injury. Here we found that aging-associated periodontitis was accompanied by lower expression of Del-1, an endogenous inhibitor of neutrophil adhesion dependent on the integrin LFA-1, and by reciprocal higher expression of interleukin 17 (IL-17). Consistent with that, IL-17 inhibited gingival endothelial cell expression of Del-1, thereby promoting LFA-1-dependent recruitment of neutrophils. Young Del-1-deficient mice developed spontaneous periodontitis that featured excessive neutrophil infiltration and IL-17 expression; disease was prevented in mice doubly deficient in Del-1 and LFA-1 or in Del-1 and the IL-17 receptor. Locally administered Del-1 inhibited IL-17 production, neutrophil accumulation and bone loss. Therefore, Del-1 suppressed LFA-1-dependent recruitment of neutrophils and IL-17-triggered inflammatory pathology and may thus be a promising therapeutic agent for inflammatory diseases.

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Figure 1: Lower expression of Del-1 in old mice is correlated with periodontal bone loss.
Figure 2: Del-1 deficiency is associated with inflammatory periodontal bone loss and neutrophil infiltration.
Figure 3: LFA-1 dependence of Del-1 deficiency–associated inflammation and bone loss.
Figure 4: Inflammatory bone loss associated with Del-1 deficiency is abrogated in mice with dual deficiency in Del-1 and IL-17R.
Figure 5: IL-17 downregulates Del-1 expression.
Figure 6: Del-1 inhibits IL-17 and periodontal inflammation in old mice.
Figure 7: Inhibition of bone loss by Del-1 and other treatments that block LFA-1 or IL-17.

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Acknowledgements

We thank T. Quertermous and R. Kundu (Stanford University School of Medicine) for Edil3−/− mice; C.M. Ballantyne (Baylor College of Medicine) for Itgal−/− mice; Amgen for Il17ra−/− mice and mAb to IL-17 (M210); Novartis for LFA878; Valentis for Del-1; and S. Gaffen for discussions and advice. Supported by the Intramural Research Program of the US National Institutes of Health, the National Cancer Institute (T.C.), Deutsche Forschungsgemeinschaft (SFB655/TPB10 and CH279/5-1 to T.C.), the Medical Faculty of the University of Dresden (MedDrive to K.-J.C.), the Medical Research Council UK (G0900408 to M.A.C.) and the Extramural Research Program of the US National Institutes of Health (DE015254, DE018292, DE021580 and DE021685 to G.H.).

Author information

Author notes

  1. Toshiharu Abe & George Hajishengallis

    Present address: Present address: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,

  2. Triantafyllos Chavakis and George Hajishengallis: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA

    Mehmet A Eskan & George Hajishengallis

  2. Center for Oral Health and Systemic Disease, University of Louisville School of Dentistry, Louisville, Kentucky, USA

    Mehmet A Eskan, Ravi Jotwani, Toshiharu Abe, Shuang Liang, Paul A Ciero, Jennifer L Krauss, Fenge Li & George Hajishengallis

  3. Division of Vascular Inflammation, Department of Medicine and Institute of Physiology, Diabetes and Kidney, Technical University Dresden, Dresden, Germany

    Jindrich Chmelar, Jong-Hyung Lim, Eun Young Choi, Kyoung-Jin Chung & Triantafyllos Chavakis

  4. Department of Medicine, Division of Endocrinology, Diabetes and Bone Diseases, Technical University Dresden, Dresden, Germany

    Martina Rauner & Lorenz C Hofbauer

  5. Department of Medicine, Graduate School, University of Ulsan, Seoul, Republic of Korea

    Eun Young Choi

  6. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Eun Young Choi & Triantafyllos Chavakis

  7. Centre for Immunology and Infectious Disease, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Ahmed Hashim & Michael A Curtis

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Contributions

M.A.E., R.J., T.A., J.C., J.-H.L., S.L., P.A.C., J.L.K., M.R., L.C.H., E.Y.C., and A.H. did research and data analysis; F.L. generated analytical tools and did tissue processing; K.-J.C. generated analytical tools; M.A.C. designed and supervised microbiological analysis; T.C. conceived of and designed the research and edited the paper together with G.H.; and G.H. conceived of, designed and supervised the research and wrote and edited the paper.

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Correspondence to George Hajishengallis.

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Eskan, M., Jotwani, R., Abe, T. et al. The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nat Immunol 13, 465–473 (2012). https://doi.org/10.1038/ni.2260

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