Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.
Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan, ROC.
Sci Rep. 2017 Jan 24;7:41123. doi: 10.1038/srep41123.
We have previously showed that IL-1β is involved in the pathogenesis of both spontaneously occurring and passively induced IgA nephropathy (IgAN) models. However, the exact causal-relationship between NLRP3 inflammasome and the pathogenesis of IgAN remains unknown. In the present study, we showed that [1] IgA immune complexes (ICs) activated NLRP3 inflammasome in macrophages involving disruption of mitochondrial integrity and induction of mitochondrial ROS, bone marrow-derived dendritic cells (BMDCs) and renal intrinsic cells; [2] knockout of NLRP3 inhibited IgA ICs-mediated activation of BMDCs and T cells; and [3] knockout of NLRP3 or a kidney-targeting delivery of shRNA of NLRP3 improved renal function and renal injury in a mouse IgAN model. These results strongly suggest that NLRP3 inflammasome serves as a key player in the pathogenesis of IgAN partly through activation of T cells and mitochondrial ROS production and that a local, kidney-targeting suppression of NLRP3 be a therapeutic strategy for IgAN.
我们之前已经表明，IL-1β 参与了自发发生和被动诱导的 IgA 肾病（IgAN）模型的发病机制。然而，NLRP3 炎性小体与 IgAN 发病机制之间的确切因果关系尚不清楚。在本研究中，我们表明：[1]IgA 免疫复合物（ICs）在巨噬细胞中激活 NLRP3 炎性小体，涉及线粒体完整性的破坏和诱导线粒体 ROS，骨髓来源的树突状细胞（BMDCs）和肾脏固有细胞；[2]NLRP3 敲除抑制 IgA ICs 介导的 BMDCs 和 T 细胞的激活；[3]NLRP3 敲除或 NLRP3 的肾脏靶向递送 shRNA 改善了 IgAN 小鼠模型的肾功能和肾脏损伤。这些结果强烈表明，NLRP3 炎性小体作为 IgAN 发病机制的关键参与者，部分通过激活 T 细胞和产生线粒体 ROS，而局部、肾脏靶向抑制 NLRP3 可能是 IgAN 的治疗策略。
