Pathogenesis of lupus nephritis: RIP3 dependent necroptosis and NLRP3 inflammasome activation
Pathogenesis of lupus nephritis: RIP3 dependent necroptosis and NLRP3 inflammasome activation
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狼疮性肾炎的发病机制：RIP3依赖性坏死性凋亡和NLRP3炎症小体激活
DOI：
10.1016/j.jaut.2019.05.014
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发表时间：
2019-09-01
影响因子：
12.8
通讯作者：
Fu, Shu Man
中科院分区：
文献类型：
--
作者：
Guo, Chaohuan;Fu, Rong;Fu, Shu Man
RIP 3激活导致坏死性凋亡和NLRP 3炎性体途径的激活。RIP 3在狼疮性肾炎（LN）中的活化尚未研究。在这项研究中，RIP 3和坏死性凋亡途径激活被证明在足细胞肾活检患者IV型LN和狼疮易感NZM 2328和MRL/lpr小鼠的患病肾脏。RIP 3激活伴随着MLKL的激活，MLKL是坏死性凋亡途径的效应分子，caspase-1是NLRP 3炎性体途径的效应分子。在NZM 2328小鼠中，随着LN的发展，很容易检测到足细胞RIP 3的激活，这表明这种激活可能在LN的发病机制中起重要作用。RIP 3特异性抑制剂GSK 872可抑制MRL/lpr小鼠LN的发生，下调RIP 3在足细胞中的活化，降低脾脏大小和重量，降低抗dsDNA抗体滴度。来自死于LN的患病NZM 2328小鼠的合并血清的IgG诱导足细胞系中的坏死性凋亡途径和NLRP 3炎性小体活化，并且这种活化被GSK 872特异性阻断。这些结果表明，在LN期间，坏死性凋亡途径和RIP 3依赖性NLRP 3炎性体途径在足细胞中被激活。抑制RIP 3激酶可能是治疗LN和系统性红斑狼疮（SLE）的一种新的治疗方法。
RIP3 activation leads to activation of necroptosis and the NLRP3 inflammasome pathways. The activation of RIP3 in lupus nephritis (LN) has not been investigated. In this study, RIP3 and necroptosis pathway activations were demonstrated in podocytes in renal biopsies from patients with class IV LN and in the diseased kidneys from lupus-prone NZM2328 and MRL/lpr mice. RIP3 activation was accompanied with the activation of MLKL, the effector molecule of the necroptosis pathway, and activation of caspase-1, the effector of the NLRP3 inflammasome pathway. Podocyte activation of RIP3 was detected readily with the development of LN in NZM2328 mice, suggesting this activation may play a significant role in the pathogenesis of LN. GSK872, a RIP3 specific inhibitor, inhibited the development of LN in MRL/lpr mice with down-regulation of RIP3 activation in podocytes, decreased the splenic sizes and weights and anti-dsDNA antibody titers. IgG from pooled sera of diseased NZM2328 mice succumbing to LN induced both the necroptosis pathway and NLRP3 inflammasome activation in a podocyte cell line and this activation was specifically blocked by GSK872. These results indicate that the necroptosis pathway and the RIP3 dependent NLRP3 inflammasome pathway are activated in podocytes during LN. Inhibition of RIP3 kinase may be a novel therapeutic approach to treat LN and systemic lupus erythematosus (SLE).