NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy
NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy
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DOI：
10.1073/pnas.1111101108
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发表时间：
2011-09-06
影响因子：
11.1
通讯作者：
Flavell, Richard A.
中科院分区：
文献类型：
--
作者：
Jin, Chengcheng;Frayssinet, Patrick;Flavell, Richard A.
促炎和分解代谢细胞因子IL-1 β通过介导滑膜炎症和软骨退变参与骨关节炎（OA）的发病机制。虽然滑膜巨噬细胞被认为是IL-1 β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和其他关节病密切相关，但HA在关节炎发病机制中的确切作用尚未得到明确证实。在这里，我们表明，HA晶体的特定大小和形状可以刺激强大的分泌促炎细胞因子IL-1 β和IL-18从鼠巨噬细胞在NLRP 3炎性小体依赖的方式。HA诱导的炎性小体活化依赖于钾外流、活性氧（ROS）的产生和溶酶体损伤，但不依赖于细胞死亡。缺乏炎性体组分的小鼠在滑膜炎的气囊模型中被保护免于HA诱导的嗜中性炎症，并且它们在关节炎的踝缺陷小鼠模型中显示出伴随自发HA沉积的关节病理学降低。此外，钙结晶阳性关节液从一些OA患者在体外炎性小体刺激活性。这些结果表明，NLRP 3炎性体介导了体外和体内HA晶体的病理作用，并表明炎性体在OA发病机制中的关键作用。
The proinflammatory and catabolic cytokine IL-1 beta has been implicated in the pathogenesis of osteoarthritis (OA) by mediating synovial inflammation and cartilage degeneration. Although synovial macrophages are suggested to be the source of IL-1 beta, the mechanism remains unclear. Ectopic deposition of hydroxyapatite (HA) crystals in joints is closely associated with OA and other arthropathies, 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-1 beta 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 ank-deficient mouse model of arthritis. Moreover, calcium crystal positive synovial fluids from some OA patients exhibited inflammasome-stimulatory 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.