Department of Medicine, University of Massachusetts Medical School, Lazare Research Building, Room 228, 364 Plantation Street, Worcester, Massachusetts 01605, USA.
J Orthop Res. 2010 Nov;28(11):1418-24. doi: 10.1002/jor.21149.
Osteolysis of bone following total hip replacement is a major clinical problem. Examination of the areas surrounding failed implants has indicated an increase in the bone-resorption-inducing cytokine, interleukin 1β (IL-1β). NALP3, a NOD-like receptor protein located in the cytosol of macrophages, signals the cleavage of pro-IL-1β into its mature, secreted form, IL-1β. Here we showed that titanium particles stimulate the NALP3 inflammasome. We demonstrated that titanium induces IL-1β secretion from macrophages. This response depended on the expression of components of the NALP3 inflammasome, including NALP3, ASC, and Caspase-1. We also showed that titanium particles trigger the recruitment of neutrophils and that this acute inflammatory response depends on the expression of the IL-1 receptor and IL-1α/β. Moreover, administration of the IL-1 receptor antagonist (IL-1Ra) diminished neutrophil recruitment in response to titanium particles. Together, these results suggest that titanium particle-induced acute inflammation is due to activation of the NALP3 inflammasome, which leads to increased IL-1β secretion and IL-1-associated signaling, including neutrophil recruitment. Efficacy of IL-1Ra treatment introduces the potential for antagonist-based therapies for implant osteolysis.
全髋关节置换术后的骨溶解是一个主要的临床问题。对失败植入物周围区域的检查表明，骨吸收诱导细胞因子白细胞介素 1β（IL-1β）增加。NALP3 是一种位于巨噬细胞质中的 NOD 样受体蛋白，可信号转导 pro-IL-1β 切割为成熟的、分泌形式的 IL-1β。在这里，我们表明钛颗粒刺激 NALP3 炎性体。我们证明钛诱导巨噬细胞分泌 IL-1β。这种反应取决于 NALP3 炎性体的组成部分的表达，包括 NALP3、ASC 和 Caspase-1。我们还表明，钛颗粒触发中性粒细胞的募集，并且这种急性炎症反应取决于 IL-1 受体和 IL-1α/β 的表达。此外，施用 IL-1 受体拮抗剂（IL-1Ra）可减少钛颗粒引起的中性粒细胞募集。总之，这些结果表明，钛颗粒诱导的急性炎症是由于 NALP3 炎性体的激活，导致 IL-1β 分泌增加和 IL-1 相关信号转导，包括中性粒细胞募集。IL-1Ra 治疗的疗效为基于拮抗剂的植入物骨溶解治疗方法提供了潜力。
