IL-17-mediated M1/M2 macrophage alteration contributes to pathogenesis of bisphosphonate-related osteonecrosis of the jaws.
IL-17-mediated M1/M2 macrophage alteration contributes to pathogenesis of bisphosphonate-related osteonecrosis of the jaws.
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DOI：
10.1158/1078-0432.ccr-13-0042
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发表时间：
2013-06-15
期刊：
影响因子：
--
通讯作者：
Le AD
中科院分区：
文献类型：
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作者：
Zhang Q;Atsuta I;Liu S;Chen C;Shi S;Shi S;Le AD
颌骨坏死（Osteonecrosis of the jaw， ONJ）是肿瘤患者使用抗吸收药物治疗的重要并发症之一。本研究探讨了il -17介导的M1/M2巨噬细胞改变在双膦酸盐相关性颌骨骨坏死（BRONJ）发病机制中的潜在作用。免疫荧光法检测人BRONJ病变局部黏膜IL-17及巨噬细胞M1、M2标记物的表达。通过静脉注射唑来膦酸钠诱导C57BL/6小鼠和多发性骨髓瘤（MM）负荷小鼠bronj样疾病，探讨IL-17水平升高与巨噬细胞M1、M2表型变化的相关性以及阻断IL-17对bronj样疾病发病机制的治疗作用。Th17细胞和IL-17细胞因子的增加与小鼠和人BRONJ病变局部粘膜M1/M2巨噬细胞比例的增加相关。令人信服的是，在患有多发性骨髓瘤的小鼠中，基底上水平升高和药物诱导的IL-17活性的结合增加了BRONJ的发生率；体外扩增的M2巨噬细胞过继性转移可逆转IL-17的全身性升高和疾病严重程度。通过特异性中和抗体或小抑制分子Laquinimod靶向IL-17，可显著降低小鼠的M1/M2比率，同时抑制bronj样疾病。在机制上，IL-17通过增加STAT-1磷酸化增强IFN-γ诱导的M1极化，同时通过抑制STAT-6激活抑制il -4介导的M2转化。这些发现在激活的il -17介导的M1巨噬细胞极化与人类疾病和小鼠模型中bronj样疾病的发展之间建立了令人信服的联系。
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 IL-17-mediated M1/M2 macrophage alterations in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ). 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 (MM)-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. Increased Th17 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 suppressed IL-4-mediated M2 conversion via inhibiting STAT-6 activation. 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.