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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy
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NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy

机译：NLRP3炎性小体在羟基磷灰石相关关节炎的发病机理中起关键作用

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摘要

The proinflammatory and catabolic cytokine IL-1f) has been implicated in the pathogenesis of osteoarthritis (OA) by mediating synovia I inflammation and cartilage degeneration. Although synovial macrophages are suggested to be the source of IL-ip, the mechanism remains unclear. Ectopic deposition of hydroxyapatite (HA) crystals in joints is closely associated with OA and other arthropa-thies, but the precise role of HA in arthritis pathogenesis has not been clearly demonstrated. Here we show that HA crystals of a particular size and shape can stimulate robust secretion of proinflammatory cytokines IL-ip and IL-18 from murine macrophages in a NLRP3 inflammasome-dependent manner. HA-induced inflammasome activation is dependent on potassium efflux, generation of reactive oxygen species (ROS), and lysosomal damage, but independent of cell death. Mice lacking the inflammasome components are protected against HA-induced neutrophilic inflammation in the air-pouch model of synovitis, and they show decreased joint pathology accompanying spontaneous HA deposition in the an/t-deficient mouse model of arthritis. Moreover, calcium crystal positive synovial fluids from some OA patients exhibited inf lammasome-stimula-tory activity in vitro. These results demonstrate that the NLRP3 inflammasome mediates the pathological effect of HA crystals in vitro and in vivo and suggest a critical role for the inflammasome in the pathogenesis of OA.
机译：促炎和分解代谢细胞因子IL-1f）通过介导滑膜I炎症和软骨变性与骨关节炎（OA）的发病机制有关。尽管滑膜巨噬细胞被认为是IL-ip的来源，但其机制仍不清楚。羟基磷灰石（HA）晶体在关节中的异位沉积与OA和其他关节炎相关，但HA在关节炎发病机理中的确切作用尚未得到明确证实。在这里，我们显示特定大小和形状的HA晶体可以以NLRP3炎性体依赖性方式刺激鼠巨噬细胞分泌促炎性细胞因子IL-ip和IL-18。 HA诱导的炎性体激活取决于钾外流，活性氧（ROS）的产生和溶酶体损伤，但与细胞死亡无关。在滑膜炎的气袋模型中，缺少炎性体成分的小鼠受到了HA诱导的嗜中性粒细胞炎症的保护，并且在关节炎的小鼠模型中，伴随自发的HA沉积，它们的关节病理性降低。而且，来自一些OA患者的钙晶体阳性滑液在体外表现出了对INFA的刺激作用。这些结果表明，NLRP3炎性小体在体外和体内介导了HA晶体的病理作用，并暗示了炎性小体在OA发病机理中的关键作用。

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