Surface RANKL of Toll-like receptor 4-stimulated human neutrophils activates osteoclastic bone resorption
Surface RANKL of Toll-like receptor 4-stimulated human neutrophils activates osteoclastic bone resorption
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DOI：
10.1182/blood-2008-09-178301
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发表时间：
2009-08-20
期刊：
影响因子：
20.3
通讯作者：
Poubelle, Patrice E.
中科院分区：
文献类型：
--
作者：
Chakravarti, Arpita;Raquil, Marie-Astrid;Poubelle, Patrice E.
脓毒症和炎性疾病中的炎性骨丢失是由于破骨细胞的活性增加，需要NF-κ B-配体（RANKL）的受体激活剂。中性粒细胞是这些疾病中的主要浸润细胞。虽然疾病的严重程度与中性粒细胞有关，但它们在骨病变演变中的作用尚不清楚。我们发现，脂多糖（LPS），Toll样受体4配体，上调人血液中性粒细胞和小鼠气囊衍生的中性粒细胞膜RANKL的表达。LPS激活的人和鼠中性粒细胞，与人单核细胞衍生的破骨细胞和RAW 264.7细胞共培养，分别刺激骨吸收。用RANKL反义RNA转染PLB-985嗜骨细胞样细胞减少破骨细胞生成。在共培养系统中，类风湿关节炎急性发作患者的滑液中性粒细胞强烈表达RANKL并激活破骨细胞生成。骨保护素（RANKL诱饵受体）抑制来自这些不同来源的中性粒细胞的破骨细胞活化。此外，通过共聚焦激光显微镜观察到中性粒细胞和破骨细胞之间的直接细胞-细胞接触。中性粒细胞膜结合RANKL的激活与含Src同源结构域的胞浆磷酸酶1的酪氨酸磷酸化相关，同时伴有细胞因子产生的下调。中性粒细胞的这些新功能的展示突出了它们在骨免疫学和炎性骨疾病治疗中的潜在作用。（血。2009; 114：1633-1644）
Inflammatory bone loss in septic and inflammatory conditions is due to increased activity of osteoclasts that requires receptor activator of NF-kappa B-ligand (RANKL). Neutrophils are the predominant infiltrating cells in these conditions. Although disease severity is linked to neutrophils, their role in evolution of bony lesions is not clear. We show that lipopolysaccharide (LPS), a toll-like receptor 4 ligand, up-regulated the expression of membrane RANKL in human blood neutrophils and murine air pouch-derived neutrophils. LPS-activated human and murine neutrophils, cocultured with human monocyte-derived osteoclasts and RAW 264.7 cells, respectively, stimulated bone resorption. Transfection of PLB-985 neutrophil-like cells with RANKL antisense RNA reduced osteoclastogenesis. Synovial fluid neutrophils of patients with exacerbation of rheumatoid arthritis strongly expressed RANKL and activated osteoclastogenesis in coculture systems. Osteoprotegerin, the RANKL decoy receptor, suppressed osteoclast activation by neutrophils from these different sources. Moreover, direct cell-cell contact between neutrophils and osteoclasts was visualized by confocal laser microscopy. Activation of neutrophil membrane-bound RANKL was linked to tyrosine phosphorylation of Src-homology domain-containing cytosolic phosphatase 1 with concomitant down-regulation of cytokine production. The demonstration of these novel functions of neutrophils highlights their potential role in osteoimmunology and in therapeutics of inflammatory bone disease. (Blood. 2009; 114: 1633-1644)