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Updated: May 12, 2026
Polarization and Characterization of M1 and M2 Human Monocyte-Derived Macrophages on Implant Surfaces
Published on: December 6, 2024
IL-17-mediated M1/M2 macrophage alteration contributes to pathogenesis of bisphosphonate-related osteonecrosis of the
Qunzhou Zhang1, Ikiru Atsuta, Shiyu Liu
1Department 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.
Purpose:
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).
Experimental Design:
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.
Insights
Interleukin-17 (IL-17) drives M1 macrophage polarization, worsening bisphosphonate-related osteonecrosis of the jaw (BRONJ). Blocking IL-17 or promoting M2 macrophages shows therapeutic potential for BRONJ.
Area of Science:
- Immunology
- Oncology
- Oral Medicine
Background:
- Osteonecrosis of the jaw (ONJ) is a serious complication for cancer patients on antiresorptive drugs.
- Bisphosphonate-related osteonecrosis of the jaw (BRONJ) pathogenesis is not fully understood.
- The role of immune cells, specifically macrophages, in BRONJ is an area of active investigation.
Purpose of the Study:
- To investigate the role of interleukin-17 (IL-17) in BRONJ development.
- To explore the impact of IL-17 on M1 and M2 macrophage polarization in BRONJ.
- To assess therapeutic strategies targeting IL-17 or macrophage phenotypes in BRONJ models.
Main Methods:
- Immunofluorescence analysis of IL-17, M1, and M2 markers in human BRONJ lesions.
- Induction of BRONJ-like disease in mice using zoledronate, with and without multiple myeloma burden.
- Evaluation of IL-17 blockade using neutralizing antibodies and laquinimod.
- Assessment of M2 macrophage adoptive transfer therapy.
Main Results:
- Elevated IL-17 and increased M1/M2 macrophage ratio observed in human and murine BRONJ lesions.
- IL-17 blockade or M2 macrophage transfer ameliorated BRONJ-like conditions in mice.
- IL-17 promotes M1 polarization via STAT-1 and inhibits M2 polarization via STAT-6.
Conclusions:
- Activated IL-17-mediated M1 macrophage polarization is a key factor in BRONJ pathogenesis.
- Targeting IL-17 or modulating macrophage polarization presents a promising therapeutic avenue for BRONJ.
