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

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.).

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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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