Baicalein ameliorates pristane-induced lupus nephritis via activating Nrf2/HO-1 in myeloid-derived suppressor cells
Baicalein ameliorates pristane-induced lupus nephritis via activating Nrf2/HO-1 in myeloid-derived suppressor cells
复制标题
黄芩素通过激活骨髓源性抑制细胞中的 Nrf2/HO-1 改善降植烷诱导的狼疮性肾炎
DOI：
10.1186/s13075-019-1876-0
复制
发表时间：
2019-04-25
影响因子：
4.9
通讯作者：
Hou, Yayi
中科院分区：
文献类型：
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作者：
Li, Dan;Shi, Guoping;Hou, Yayi
狼疮性肾炎(LN)是系统性红斑狼疮(SLE)的典型表现。一些研究表明，髓系来源的抑制细胞(MDSCs)在SLE的过程中起着至关重要的调节作用。MDSC在肾脏的浸润以及炎症和氧化应激导致LN的加速和恶化。核因子E2相关因子2(NRF2)被认为是抗氧化反应的主要调节因子。黄芩素是一种黄酮类化合物，具有已知的抗炎和抗氧化作用。然而，在Pristane诱导的狼疮小鼠狼疮模型中，黄芩素对MDSCs、炎症反应和氧化应激的影响未见报道。检测NLRP3炎性小体的激活和核因子-B的磷酸化，以及活性氧(ROS)的产生和Nrf2的激活。检测骨髓间充质干细胞的比例和功能变化。分析了黄芩素对脂多糖(LPS)诱导的MDSCs中ROS的产生及Nrf2/HO-1、NLRP3炎症体和核因子-B磷酸化信号通路的影响。结果黄芩素可减少狼疮小鼠的蛋白尿，减轻肾功能损害和肾组织病理改变，包括固有细胞增殖、细胞新月体和足细胞损伤以及肾小球肾炎活动。此外，黄芩素还可下调NLRP3炎症体的激活和ROS或核因子-B的磷酸化水平，并增强Nrf2的激活。值得注意的是，黄芩素抑制了狼疮小鼠骨髓间充质干细胞的扩张，并改善了干细胞的功能。通过对脂多糖诱导的MDSCs的体外分析，发现黄芩素具有与诱导Nrf2/HO-1信号转导和抑制NLRP3炎症反应相一致的细胞保护作用。结论黄芩素减轻了Pristane诱导的LN的症状，提示其缓解作用可能与抑制MDSC的扩增，调节Nrf2/HO-1信号和NLRP3表达的平衡有关。
IntroductionLupus nephritis (LN) is a representative manifestation in systemic lupus erythematosus (SLE). Some studies have shown that myeloid-derived suppressor cells (MDSCs) play a vital role in the regulation of the SLE process. MDSC infiltration in the kidney as well as inflammation and oxidative stress provokes the acceleration and deterioration of LN. Nuclear factor E2-related factor 2 (Nrf2) is thought to be a major regulator of the antioxidant response. Baicalein is a flavonoid with known anti-inflammatory effects and antioxidant response. However, the effects of baicalein on MDSCs, inflammation, and oxidative stress are not evaluated in the development of pristane-induced LN in mice.MethodsThe renoprotective effect of baicalein was detected in a pristane-induced lupus mice model. NLRP3 inflammasome activation and NF-B phosphorylation as well as reactive oxygen species (ROS) production and Nrf2 activation were examined. The percentages and function changes of MDSCs were measured. The possible mechanisms of the underlying effects of baicalein on ROS production and signaling pathways of Nrf2/heme-oxygenase (HO)-1, NLRP3 inflammasome, and NF-B phosphorylation in lipopolysaccharide (LPS)-primed MDSCs were analyzed.ResultsBaicalein reduced proteinuria and attenuated renal function impairment and renal histopathology including intrinsic cell proliferation, cellular crescents, and podocyte injury as well as glomerulonephritis activity in lupus mice. Moreover, baicalein downregulated the activation of NLRP3 inflammasome and levels of ROS or NF-B phosphorylation, and it enhanced Nrf2 activation. Of note, baicalein inhibited the expansion of MDSCs and improved the function of MDSCs in lupus mice. Through analyzing LPS-primed MDSCs in vitro, baicalein was found to exhibit cytoprotective effects coincident with the induction of Nrf2/HO-1 signaling and the suppression of the NLRP3 inflammasome.ConclusionThe data show that baicalein alleviates the symptoms of pristane-induced LN and suggest that the alleviation may be attributed to inhibition of MDSC expansion and regulation of the balance of the Nrf2/HO-1 signal and NLRP3 expression in MDSCs.