{"title":"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。","authors":"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","doi":"10.1002/art.43380","DOIUrl":null,"url":null,"abstract":"BACKGROUND\r\nCaspase-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.\r\n\r\nMETHODS\r\nThe 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.\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. Mechanically, galectin-3 and interleukin-10 (IL-10) are essential for MSCs to inhibit noncanonical pyroptosis of LN macrophages.\r\n\r\nCONCLUSIONS\r\nOur 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.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"35 1","pages":""},"PeriodicalIF":10.9000,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mesenchymal Stromal Cell Therapy Alleviates Lupus Nephritis Through Inhibiting Caspase-4/5/11-mediated Noncanonical Pyroptosis in Macrophages.\",\"authors\":\"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\",\"doi\":\"10.1002/art.43380\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"BACKGROUND\\r\\nCaspase-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.\\r\\n\\r\\nMETHODS\\r\\nThe 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.\\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. Mechanically, galectin-3 and interleukin-10 (IL-10) are essential for MSCs to inhibit noncanonical pyroptosis of LN macrophages.\\r\\n\\r\\nCONCLUSIONS\\r\\nOur 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.\",\"PeriodicalId\":129,\"journal\":{\"name\":\"Arthritis & Rheumatology\",\"volume\":\"35 1\",\"pages\":\"\"},\"PeriodicalIF\":10.9000,\"publicationDate\":\"2025-09-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Arthritis & Rheumatology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/art.43380\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RHEUMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Arthritis & Rheumatology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/art.43380","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
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.
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.