Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.

Abstract

Leukocyte adhesion deficiency type I (LAD-I), a disease syndrome associated with frequent microbial infections, is caused by mutations on the CD18 subunit of β₂ integrins. LAD-I is invariably associated with severe periodontal bone loss, which historically has been attributed to the lack of neutrophil surveillance of the periodontal infection. We provide an alternative mechanism by showing that the cytokine interleukin-17 (IL-17) plays a major role in the oral pathology of LAD-I. Defective neutrophil recruitment in LAD-I patients or in LFA-1 (CD11a/CD18)-deficient mice--which exhibit the LAD-I periodontal phenotype--was associated with excessive production of predominantly T cell-derived IL-17 in the periodontal tissue, although innate lymphoid cells also contributed to pathological IL-17 elevation in the LFA-1-deficient mice. Local treatment with antibodies to IL-17 or IL-23 in LFA-1-deficient mice not only blocked inflammatory periodontal bone loss but also caused a reduction in the total bacterial burden, suggesting that the IL-17-driven pathogenesis of LAD-I periodontitis leads to dysbiosis. Therefore, our findings support an IL-17-targeted therapy for periodontitis in LAD-I patients.

• Authors: Niki M Moutsopoulos, Joanne Konkel, Mojgan Sarmadi, Mehmet A Eskan, Teresa Wild, Nicolas Dutzan, Loreto Abusleme, Camille Zenobia, Kavita B Hosur, Toshiharu Abe, Gulbu Uzel, Wanjun Chen, Triantafyllos Chavakis, Steven M Holland, George Hajishengallis
• Journal: Science translational medicine (Sci Transl Med) Vol. 6 Issue 229 Pg. 229ra40 (Mar 26 2014) ISSN: 1946-6242 [Electronic] United States
• PMID: 24670684 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-17
• Interleukin-23
• Lymphocyte Function-Associated Antigen-1

Topics

• Adolescent
• Animals
• Bone Resorption (complications, pathology)
• Cell Adhesion
• Child
• Gene Expression Profiling
• Humans
• Inflammation (complications, genetics, pathology)
• Interleukin-17 (metabolism)
• Interleukin-23 (metabolism)
• Leukocyte-Adhesion Deficiency Syndrome (complications, genetics, pathology)
• Lymphocyte Function-Associated Antigen-1 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neutrophil Infiltration
• Periodontitis (complications, genetics, microbiology, pathology)