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

Abstract

Aging is linked to increased 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 diminished expression of Del-1 (EDIL3), an endogenous inhibitor of LFA-1 integrin-dependent neutrophil adhesion, and by a reciprocal increase in IL-17 expression. Consistently, IL-17 inhibited gingival endothelial cell expression of Del-1, thereby promoting LFA-1-dependent neutrophil recruitment. Young Del-1-deficient mice developed spontaneous periodontitis featuring excessive neutrophil infiltration and IL-17 expression; disease was prevented in Del-1–LFA-1 and Del-1–IL-17 receptor double-deficient mice. Locally administered Del-1 inhibited IL-17 production, neutrophil accumulation, and bone loss. Therefore, Del-1 suppresses LFA-1-dependent neutrophil recruitment and IL-17-triggered inflammatory pathology and may thus be a promising therapeutic for inflammatory diseases.

The effect of periodontal scaling and root polishing on serum IL-17E concentrations and the IL-17A:IL-17E ratio

“…However, an excessive IL-17A response has been demonstrated to drive inflammatory alveolar bone loss in an ageing mouse model of periodontitis [2]. Therefore an effective, but balanced, IL-17A response is required for the protection of the oral mucosa against periodontal pathogens.…”

Porphyromonas gingivalis-derived Lysine Gingipain Enhances Osteoclast Differentiation Induced by Tumor Necrosis Factor-α and Interleukin-1β but Suppresses That by Interleukin-17A

“…It was also reported that alveolar bone loss induced by P. gingivalis infection in IL-6-deficient mice was milder than that in wild-type mice (37). Also, in addition to its role as a chemotactic factor for neutrophils, IL-17A induces periodontal bone destruction (38). These cytokines stimulate osteoblasts to express RANKL, which in turn induces differentiation and activation of osteoclasts via RANKL-RANK interaction (8 -11).…”

Neutrophil Role in Periodontal Disease

“…Del-1 is another promising candidate molecule to be used therapeutically to prevent neutrophil recruitment and bone loss associated with periodontal inlammation [17]. Since Del-1 blocks LFA-1 binding to its ligand ICAM-1 and prevents neutrophil transmigration [50], it could be administered to inlamed tissues, to reduce neutrophil recruitment, and to reduce inlammation.…”

“…Some chemoatractants for neutrophils are activated by complement components, such as the anaphylatoxin C5a, and bacterial components, such as formyl-methionyl-leucyl-phenylalanine (fMLF). Recently, it has been discovered that the leukocyte adhesion cascade is also negatively regulated by endogenous inhibitors such as Del-1 (developmental endothelial locus-1), pentraxin 3, and growthdiferentiation factor 15 [17].…”