Procyanidin B2 prevents lupus nephritis development in mice by inhibiting NLRP3 inflammasome activation
Abstract
Lupus nephritis (LN) is a multifactorial event that contributes to the long-term mortality of systemic lupus erythematosus (SLE). Activation of NLRP3 inflammasome has been known to play a role in SLE pathogenesis. We evaluated the renal protection effects of procyanidin B2 (PCB2) and the involvement of NLRP3 in a mouse model involving MRL/lpr and MRL/MpJ mice. Kidney injury was evaluated by measuring the renal clinical and pathological features, renal immune complex deposition, and serum anti-double-stranded (anti-dsDNA) Abs. ELISA and Western blotting were used to detect NLRP3 inflammasome activation and IL-1β/IL-18 production. NLRP3 gene silencing was introduced into MRL/lpr mice by short hairpin RNA, and the renal damage was compared with the treatment of PCB2. PCB2 remarkably reduced renal damage in MRL/lpr mice, reflected by the reduced proteinuria, and serum levels of blood urea nitrogen and creatinine, as well as pathological features with less renal injury. PCB2 significantly reduced renal immune complex deposition and serum anti-dsDNA levels, notably inhibited the NLRP3 inflammasome activation, and reduced the renal and serum levels of IL-1β and IL-18 in MRL/lpr mice compared with those of NLRP3 gene-silenced MRL-lpr mice. PCB2 significantly suppressed LN in MRL-lpr mice by inhibiting the activation of NLRP3 inflammasome and subsequent IL-1β and IL-18 production. This finding explores a novel mechanism by which procyanidin exerts inflammatory suppression effects and its clinical benefits in LN prevention.
狼疮肾炎(LN)是一个多因素事件，有助于系统性红斑狼疮(SLE)的长期死亡率。NLRP3炎症小体的激活在SLE发病中起作用。在MRL/lpr和MRL/MpJ小鼠模型中，我们评估了原花青素B2 (PCB2)和NLRP3的肾保护作用。通过测量肾脏临床和病理特征、肾脏免疫复合物沉积和血清抗双链(抗dsdna)抗体来评估肾脏损伤。采用ELISA和Western blotting检测NLRP3炎症小体激活和IL-1β/IL-18的产生。采用短发夹RNA将NLRP3基因沉默导入MRL/lpr小鼠，并与PCB2治疗比较其肾损害情况。PCB2显著降低MRL/lpr小鼠的肾损害，表现为蛋白尿减少，血清尿素氮和肌酐水平降低，病理特征明显，肾损害较小。与NLRP3基因沉默的MRL-lpr小鼠相比，PCB2显著降低MRL/lpr小鼠肾脏免疫复合物沉积和血清抗dsdna水平，显著抑制NLRP3炎性小体的激活，并降低IL-1β和IL-18的肾脏和血清水平。PCB2通过抑制NLRP3炎性小体的激活和随后IL-1β和IL-18的产生，显著抑制MRL-lpr小鼠中LN的表达。这一发现探索了原花青素发挥炎症抑制作用的新机制及其在预防LN中的临床益处。
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