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

Nat Immunol. 2012 Mar 25;13(5):465-73. doi: 10.1038/ni.2260.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / immunology
  • Alveolar Bone Loss / immunology*
  • Animals
  • Carrier Proteins / immunology
  • Carrier Proteins / metabolism*
  • Carrier Proteins / pharmacology
  • Cell Adhesion / drug effects
  • Endothelial Cells / drug effects
  • Endothelial Cells / immunology
  • Female
  • Integrins / antagonists & inhibitors
  • Integrins / immunology
  • Integrins / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-17 / antagonists & inhibitors*
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism*
  • 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 / immunology
  • Neutrophils / metabolism
  • Periodontal Atrophy / immunology
  • Periodontal Atrophy / metabolism
  • Periodontitis / immunology
  • Periodontitis / metabolism*
  • Periodontitis / therapy
  • Receptors, Interleukin-17 / deficiency
  • Receptors, Interleukin-17 / metabolism

Substances

  • Carrier Proteins
  • Edil3 protein, mouse
  • Integrins
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-17
  • Lymphocyte Function-Associated Antigen-1
  • Receptors, Interleukin-17