Yaqi Luan, Weiwei He, Kunmao Jiang, Shenghui Qiu, Lan Jin, Xinrui Mao, Ying Huang, Wentao Liu, Jingyuan Cao, Lai Jin, Rong Wang
{"title":"低聚原花青素抑制中性粒细胞胞外捕获物,通过肠道-肾脏轴缓解化疗引起的慢性肾损伤","authors":"Yaqi Luan, Weiwei He, Kunmao Jiang, Shenghui Qiu, Lan Jin, Xinrui Mao, Ying Huang, Wentao Liu, Jingyuan Cao, Lai Jin, Rong Wang","doi":"10.1101/2024.09.03.610977","DOIUrl":null,"url":null,"abstract":"Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic, but its use is limited by adverse effects in normal tissues. In particular, cisplatin administration often damages the kidneys. However, little is known about how to alleviate cisplatin-induced chronic kidney disease (CKD) specifically. Here, we found that repeated low-dose cisplatin (RLDC) recruited neutrophils to the proximal tubule, thereby promoting the progression of CKD in the mouse model. Mechanically, cisplatin destroyed the intestinal epithelium, which induced dysregulation of gut flora and intestinal leakage. It triggered Neutrophil extracellular traps (NETs) formation, accumulating in the proximal tubule and promotes chronic inflammation and fibrosis, and promotes chronic hypoxia, leading to poor regeneration that promotes CKD progression. NETs provided a scaffold for tissue factors (TF) adhesion and metalloid-matrix protease 9 (MMP-9) activation, which triggers local ischemia and hypoxia. In addition, NETs promoted inflammasome construction through NOD-like receptor thermal protein domain associated protein 3 (NLRP3) shear and secretion of mature interleukin-18 (IL18), which subsequently released interferon-γ (IFN-γ), contributing to renal interstitial fibrosis. We proposed that oligomeric procyanidins (OPC) ameliorated RLDC-induced CKD through multi-targeting damage induced by NETs. OPC ameliorated microcirculatory disorders and inhibited inflammation by protecting the intestinal mucosa barrier and subsequent bacterial endotoxin translocation. Furthermore, we found that OPC directly blocked LPS & cisplatin-induced NETs formation in vitro. In summary, NETs play a pivotal role in CKD, which OPC alleviates by inhibiting TF/MMP-9 and IL-18-NLRP3 pathways. OPCs protect the kidney by inhibiting NETs production through anti-inflammatory and antioxidant activities and restoring the balance of the intestinal flora.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"79 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Inhibition on neutrophil extracellular traps by oligomeric procyanidins alleviate chemotherapy-induced chronic kidney injury via gut-kidney axis\",\"authors\":\"Yaqi Luan, Weiwei He, Kunmao Jiang, Shenghui Qiu, Lan Jin, Xinrui Mao, Ying Huang, Wentao Liu, Jingyuan Cao, Lai Jin, Rong Wang\",\"doi\":\"10.1101/2024.09.03.610977\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic, but its use is limited by adverse effects in normal tissues. In particular, cisplatin administration often damages the kidneys. However, little is known about how to alleviate cisplatin-induced chronic kidney disease (CKD) specifically. Here, we found that repeated low-dose cisplatin (RLDC) recruited neutrophils to the proximal tubule, thereby promoting the progression of CKD in the mouse model. Mechanically, cisplatin destroyed the intestinal epithelium, which induced dysregulation of gut flora and intestinal leakage. It triggered Neutrophil extracellular traps (NETs) formation, accumulating in the proximal tubule and promotes chronic inflammation and fibrosis, and promotes chronic hypoxia, leading to poor regeneration that promotes CKD progression. NETs provided a scaffold for tissue factors (TF) adhesion and metalloid-matrix protease 9 (MMP-9) activation, which triggers local ischemia and hypoxia. In addition, NETs promoted inflammasome construction through NOD-like receptor thermal protein domain associated protein 3 (NLRP3) shear and secretion of mature interleukin-18 (IL18), which subsequently released interferon-γ (IFN-γ), contributing to renal interstitial fibrosis. We proposed that oligomeric procyanidins (OPC) ameliorated RLDC-induced CKD through multi-targeting damage induced by NETs. OPC ameliorated microcirculatory disorders and inhibited inflammation by protecting the intestinal mucosa barrier and subsequent bacterial endotoxin translocation. Furthermore, we found that OPC directly blocked LPS & cisplatin-induced NETs formation in vitro. In summary, NETs play a pivotal role in CKD, which OPC alleviates by inhibiting TF/MMP-9 and IL-18-NLRP3 pathways. OPCs protect the kidney by inhibiting NETs production through anti-inflammatory and antioxidant activities and restoring the balance of the intestinal flora.\",\"PeriodicalId\":501182,\"journal\":{\"name\":\"bioRxiv - Immunology\",\"volume\":\"79 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-09-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"bioRxiv - Immunology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2024.09.03.610977\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"bioRxiv - Immunology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.09.03.610977","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Inhibition on neutrophil extracellular traps by oligomeric procyanidins alleviate chemotherapy-induced chronic kidney injury via gut-kidney axis
Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic, but its use is limited by adverse effects in normal tissues. In particular, cisplatin administration often damages the kidneys. However, little is known about how to alleviate cisplatin-induced chronic kidney disease (CKD) specifically. Here, we found that repeated low-dose cisplatin (RLDC) recruited neutrophils to the proximal tubule, thereby promoting the progression of CKD in the mouse model. Mechanically, cisplatin destroyed the intestinal epithelium, which induced dysregulation of gut flora and intestinal leakage. It triggered Neutrophil extracellular traps (NETs) formation, accumulating in the proximal tubule and promotes chronic inflammation and fibrosis, and promotes chronic hypoxia, leading to poor regeneration that promotes CKD progression. NETs provided a scaffold for tissue factors (TF) adhesion and metalloid-matrix protease 9 (MMP-9) activation, which triggers local ischemia and hypoxia. In addition, NETs promoted inflammasome construction through NOD-like receptor thermal protein domain associated protein 3 (NLRP3) shear and secretion of mature interleukin-18 (IL18), which subsequently released interferon-γ (IFN-γ), contributing to renal interstitial fibrosis. We proposed that oligomeric procyanidins (OPC) ameliorated RLDC-induced CKD through multi-targeting damage induced by NETs. OPC ameliorated microcirculatory disorders and inhibited inflammation by protecting the intestinal mucosa barrier and subsequent bacterial endotoxin translocation. Furthermore, we found that OPC directly blocked LPS & cisplatin-induced NETs formation in vitro. In summary, NETs play a pivotal role in CKD, which OPC alleviates by inhibiting TF/MMP-9 and IL-18-NLRP3 pathways. OPCs protect the kidney by inhibiting NETs production through anti-inflammatory and antioxidant activities and restoring the balance of the intestinal flora.