title: IL-17-mediated M1/M2 macrophage alteration contributes to pathogenesis of bisphosphonate-related osteonecrosis of the jaws.
abstract: OBJECTIVE
  Osteonecrosis of the jaw (ONJ) is emerging as one of the important complications in cancer patients treated with antiresorptive agents. This study explored the potential role of interleukin (IL)-17-mediated M1/M2 macrophage alterations in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ).
  
  
  METHODS
  The expression of IL-17 and M1 and M2 macrophage markers at the local mucosal site of human BRONJ lesions was examined by immunofluorescence studies. BRONJ-like disease was induced in C57BL/6 mice and multiple myeloma-burdened mice by intravenous injection of zoledronate to evaluate the correlation of elevated IL-17 levels with changes in M1 and M2 macrophage phenotypes and the therapeutic effects of blocking IL-17 on pathogenesis of BRONJ-like disease.
  
  
  RESULTS
  Increased T-helper (TH)17 cells and IL-17 cytokine correlate with an increase in M1/M2 macrophages ratio at the local mucosal site of both murine and human BRONJ lesion. Convincingly, in mice burdened with multiple myeloma, a combination of elevated suprabasal level and drug-induced IL-17 activity augmented the incidence of BRONJ; both systemic increase of IL-17 and disease severity could be reversed by adoptive transfer of ex vivo expanded M2 macrophages. Targeting IL-17 via specific neutralizing antibodies or a small inhibitory molecule, laquinimod, significantly decreased M1/M2 ratio and concomitantly suppressed BRONJ-like condition in mice. Mechanistically, IL-17 enhanced IFN-γ-induced M1 polarization through augmenting STAT-1 phosphorylation while suppressing IL-4-mediated M2 conversion via inhibiting STAT-6 activation.
  
  
  CONCLUSIONS
  These findings have established a compelling linkage between activated IL-17-mediated polarization of M1 macrophages and the development of BRONJ-like conditions in both human disease and murine models.
authors.affiliation: Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania School of Dental Medicine and Penn Medicine Hospital of University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Qunzhou
authors.initials: Q
authors.lastname: Zhang
authors.forename: Ikiru
authors.initials: I
authors.lastname: Atsuta
authors.forename: Shiyu
authors.initials: S
authors.lastname: Liu
authors.forename: Chider
authors.initials: C
authors.lastname: Chen
authors.forename: Shihong
authors.initials: S
authors.lastname: Shi
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
authors.forename: Anh D
authors.initials: AD
authors.lastname: Le
mesh_terms: D000818:Animals; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D004164:Diphosphonates / Q000008:administration & dosage; D004195:Disease Models, Animal; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D007568:Jaw / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D020381:Interleukin-17; D000077211:Zoledronic Acid