间充质间质细胞治疗通过抑制caspase -4/5/11介导的巨噬细胞非典型焦亡来缓解狼疮性肾炎。

IF 10.9 1区 医学 Q1 RHEUMATOLOGY
Sha Liu,Zhikang Wang,Yue Zhang,Panpan Zhou,Huimin Zhu,Yang Hang,Xue Xu,Xiaojun Tang,Genhong Yao,Dandan Wang,Linyu Geng,Weiwei Chen,Lingyun Sun
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Blood samples from 19 refractory SLE patients receiving MSCs transplantation (MSCT) were collected. Caspase-11 inhibitor wedelolactone and MSCs were administered to MRL/lpr mice to examine the therapeutic efficacy. MSCs were co-cultured with macrophages from MRL/lpr mice to explore effects and related mechanisms.\r\n\r\nRESULTS\r\nNoncanonical pyroptosis signaling was activated in macrophages and kidney tissues from humans and mice with LN. The expression level of caspase-4 was increased and positively correlated with the active index and chronic index in the kidneys of LN patients. The end products of pyroptosis directly induced cell death and reduced functional markers expression in murine podocytes. The caspase-11 inhibitor effectively alleviated renal damage in lupus mice. MSCT significantly deactivated pyroptosis signaling both in patients and lupus-prone mice. 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引用次数: 0

摘要

caspase -4/5/11介导的非典型焦亡在病理条件下成为免疫反应的一个促进因素。然而,它在狼疮性肾炎(LN)发展中的确切作用在很大程度上仍然未知。虽然间充质间质细胞(MSCs)已显示出治疗LN的良好效果,但MSCs是否影响巨噬细胞的焦亡仍不清楚。本研究旨在阐明caspase-4/5/11介导的巨噬细胞非典型焦亡在LN发病过程中的作用,探讨MSCs对巨噬细胞的影响。方法观察LN患者和小鼠巨噬细胞中非典型焦亡蛋白的表达水平。收集19例接受骨髓间充质干细胞移植(MSCT)的难治性SLE患者的血液样本。用Caspase-11抑制剂韦地内酯和MSCs治疗MRL/lpr小鼠,观察其治疗效果。将MSCs与MRL/lpr小鼠巨噬细胞共培养,探讨其作用机制。结果LN患者的巨噬细胞和肾组织中非典型焦亡信号被激活。LN患者肾脏中caspase-4表达水平升高,且与活跃指数和慢性指数呈正相关。焦亡的最终产物直接诱导细胞死亡并降低小鼠足细胞功能标志物的表达。caspase-11抑制剂可有效减轻狼疮小鼠肾损害。在患者和狼疮易感小鼠中,MSCT显著地使焦亡信号失活。机械上,半凝集素-3和白细胞介素-10 (IL-10)是MSCs抑制LN巨噬细胞非典型焦亡所必需的。结论MSCT通过抑制caspase-4/5/11介导的巨噬细胞焦亡,可能通过分泌半乳糖凝集素-3和IL-10来改善LN。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mesenchymal Stromal Cell Therapy Alleviates Lupus Nephritis Through Inhibiting Caspase-4/5/11-mediated Noncanonical Pyroptosis in Macrophages.
BACKGROUND Caspase-4/5/11 mediated noncanonical pyroptosis emerges as a contributing factor in immune responses under pathological conditions. However, its precise role in the development of lupus nephritis (LN) remains largely unknown. Although mesenchymal stromal cells (MSCs) have demonstrated promising therapeutic effects on LN, whether MSCs influence pyroptosis in macrophages remains unknown. This study aimed to elucidate the role of caspase-4/5/11-mediated noncanonical pyroptosis in macrophages during the pathogenesis of LN and explore the impact of MSCs on macrophages. METHODS The expression level of noncanonical pyroptosis in macrophages was assessed in patients and mice with LN. Blood samples from 19 refractory SLE patients receiving MSCs transplantation (MSCT) were collected. Caspase-11 inhibitor wedelolactone and MSCs were administered to MRL/lpr mice to examine the therapeutic efficacy. MSCs were co-cultured with macrophages from MRL/lpr mice to explore effects and related mechanisms. RESULTS Noncanonical pyroptosis signaling was activated in macrophages and kidney tissues from humans and mice with LN. The expression level of caspase-4 was increased and positively correlated with the active index and chronic index in the kidneys of LN patients. The end products of pyroptosis directly induced cell death and reduced functional markers expression in murine podocytes. The caspase-11 inhibitor effectively alleviated renal damage in lupus mice. MSCT significantly deactivated pyroptosis signaling both in patients and lupus-prone mice. Mechanically, galectin-3 and interleukin-10 (IL-10) are essential for MSCs to inhibit noncanonical pyroptosis of LN macrophages. CONCLUSIONS Our findings showed that MSCT ameliorates LN by inhibiting the caspase-4/5/11-mediated pyroptosis in macrophages, possibly via secreting galectin-3 and IL-10.
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来源期刊
Arthritis & Rheumatology
Arthritis & Rheumatology RHEUMATOLOGY-
CiteScore
20.90
自引率
3.00%
发文量
371
期刊介绍: Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.
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