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

• Published in: Nature immunology Vol. 13; no. 5; pp. 465 - 473
• Main Authors: Eskan, Mehmet A, Jotwani, Ravi, Abe, Toshiharu, Chmelar, Jindrich, Lim, Jong-Hyung, Liang, Shuang, Ciero, Paul A, Krauss, Jennifer L, Li, Fenge, Rauner, Martina, Hofbauer, Lorenz C, Choi, Eun Young, Chung, Kyoung-Jin, Hashim, Ahmed, Curtis, Michael A, Chavakis, Triantafyllos, Hajishengallis, George
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-05-2012; Nature Publishing Group
• Subjects: 631/250/249/2510; 631/250/251; 631/250/256; 692/420; Adhesion; Aging; Aging - immunology; Alveolar Bone Loss - immunology; Animals; Biomedical and Life Sciences; Biomedicine; Calcium-Binding Proteins; Carrier Proteins - immunology; Carrier Proteins - metabolism; Carrier Proteins - pharmacology; Cell Adhesion - drug effects; Cell Adhesion Molecules; Disease susceptibility; Endothelial Cells - drug effects; Endothelial Cells - immunology; Female; Immunology; Infectious Diseases; Infiltration; Integrins; Integrins - antagonists & inhibitors; Integrins - immunology; Integrins - metabolism; Intercellular Signaling Peptides and Proteins; Interleukin-17 - antagonists & inhibitors; Interleukin-17 - immunology; Interleukin-17 - metabolism; Interleukins; Lymphocyte Function-Associated Antigen-1 - immunology; Lymphocyte Function-Associated Antigen-1 - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration - drug effects; Neutrophil Infiltration - immunology; Neutrophils; Neutrophils - immunology; Neutrophils - metabolism; Pathology; Periodontal Atrophy - immunology; Periodontal Atrophy - metabolism; Periodontitis - immunology; Periodontitis - metabolism; Periodontitis - therapy; Properties; Receptors, Interleukin-17 - deficiency; Receptors, Interleukin-17 - metabolism; United States
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.2260

Periodontitis is associated with aging and more neutrophil-mediated tissue pathology. Hajishengallis and colleagues show an inverse correlation between interleukin 17 expression and Del-1 expression in gingival tissues, with Del-1 protecting tissues from neutrophil infiltration.
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.