title: 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.
authors.affiliation: Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Mehmet A
authors.initials: MA
authors.lastname: Eskan
authors.forename: Ravi
authors.initials: R
authors.lastname: Jotwani
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Abe
authors.forename: Jindrich
authors.initials: J
authors.lastname: Chmelar
authors.forename: Jong-Hyung
authors.initials: JH
authors.lastname: Lim
authors.forename: Shuang
authors.initials: S
authors.lastname: Liang
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ciero
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Krauss
authors.forename: Fenge
authors.initials: F
authors.lastname: Li
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Choi
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Chung
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hashim
authors.forename: Michael A
authors.initials: MA
authors.lastname: Curtis
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.forename: George
authors.initials: G
authors.lastname: Hajishengallis
mesh_terms: D000375:Aging / Q000276:immunology; D016301:Alveolar Bone Loss / Q000276:immunology*; D000818:Animals; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D016023:Integrins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D055093:Periodontal Atrophy / Q000276:immunology / Q000378:metabolism; D010518:Periodontitis / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D053722:Receptors, Interleukin-17 / Q000172:deficiency / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; C491706:Edil3 protein, mouse; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D016169:Lymphocyte Function-Associated Antigen-1; D053722:Receptors, Interleukin-17