LXA4 protected mice from renal ischemia/reperfusion injury by promoting IRG1/Nrf2 and IRAK-M-TRAF6 signal pathways

作者全名："Tie, Hongtao; Kuang, Ge; Gong, Xia; Zhang, Lidan; Zhao, Zizuo; Wu, Shengwang; Huang, Wenya; Chen, Xiahong; Yuan, Yinglin; Li, Zhenhan; Li, Hongzhong; Zhang, Li; Wan, Jingyuan; Wang, Bin"

作者地址："[Tie, Hongtao] Chongqing Med Univ, Dept Cardiothorac Surg, Affiliated Hosp 1, Chongqing, Peoples R China; [Tie, Hongtao; Kuang, Ge; Chen, Xiahong; Wan, Jingyuan; Wang, Bin] Chongqing Med Univ, Chongqing Key Lab Biochem & Mol Pharmacol, Chongqing, Peoples R China; [Gong, Xia] Chongqing Med Univ, Dept Anat, Chongqing, Peoples R China; [Zhang, Lidan; Zhao, Zizuo; Wang, Bin] Chongqing Med Univ, Dept Anesthesiol, Affiliated Hosp 1, Chongqing, Peoples R China; [Wu, Shengwang] Army Med Univ, Xinqiao Hosp, Dept Hematol, Chongqing, Peoples R China; [Huang, Wenya] Yiling Women & Childrens Hosp Yichang City, Yichang, Hubei, Peoples R China; [Yuan, Yinglin] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Clin Immunol Translat Med Key Lab Sichuan Prov, Chengdu, Peoples R China; [Li, Zhenhan] Chongqing Tradit Chinese Med Hosp, Dept Endocrinol, Chongqing, Peoples R China; [Zhang, Li] Chongqing Med Univ, Chongqing Key Lab Mol Oncol & Epigenet, Affiliated Hosp 1, Chongqing, Peoples R China; [Zhang, Li; Wan, Jingyuan] Chongqing Med Univ, Dept Pathophysiol, Chongqing, Peoples R China; [Wan, Jingyuan] Chongqing Med Univ, Sch Pharm, Dept Pharmacol, Chongqing, Peoples R China"

通信作者："Wan, JY; Wang, B (通讯作者)，Chongqing Med Univ, Chongqing Key Lab Biochem & Mol Pharmacol, Chongqing, Peoples R China."

来源：CLINICAL IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001202519600001

JCR分区：Q1

影响因子：8.6

年份：2024

卷号：261

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Ischemia/reperfusion; Lipoxin A4; IRAK-M; IRG1; Nrf2

摘要："Excessive inflammatory response and increased oxidative stress play an essential role in the pathophysiology of ischemia/reperfusion (I/R)-induced acute kidney injury (IRI-AKI). Emerging evidence suggests that lipoxin A4 (LXA4), as an endogenous negative regulator in inflammation, can ameliorate several I/R injuries. However, the mechanisms and effects of LXA4 on IRI-AKI remain unknown. In this study, A bilateral renal I/R mouse model was used to evaluate the role of LXA4 in wild-type, IRG1 knockout, and IRAK-M knockout mice. Our results showed that LXA4, as well as 5-LOX and ALXR, were quickly induced, and subsequently decreased by renal I/R. LXA4 pretreatment improved renal I/R-induced renal function impairment and renal damage and inhibited inflammatory responses and oxidative stresses in mice kidneys. Notably, LXA4 inhibited I/R-induced the activation of TLR4 signal pathway including decreased phosphorylation of TAK1, p36, and p65, but did not affect TLR4 and p-IRAK-1. The analysis of transcriptomic sequencing data and immunoblotting suggested that innate immune signal molecules interleukin-1 receptor-associated kinase-M (IRAK-M) and immunoresponsive gene 1 (IRG1) might be the key targets of LXA4. Further, the knockout of IRG1 or IRAK-M abolished the beneficial effects of LXA4 on IRI-AKI. In addition, IRG1 deficiency reversed the up-regulation of IRAK-M by LXA4, while IRAK-M knockout had no impact on the IRG1 expression, indicating that IRAK-M is a downstream molecule of IRG1. Mechanistically, we found that LXA4-promoted IRG1-itaconate not only enhanced Nrf2 activation and increased HO-1 and NQO1, but also upregulated IRAK-M, which interacted with TRAF6 by competing with IRAK-1, resulting in deactivation of TLR4 downstream signal in IRI-AKI. These data suggested that LXA4 protected against IRI-AKI via promoting IRG1/Itaconate-Nrf2 and IRAK-M-TRAF6 signaling pathways, providing the rationale for a novel strategy for preventing and treating IRI-AKI."

基金机构："National Natural Science Foundation of China [CSTB2022NSCQ-MSX0840]; Natural Science Foundation of Chongqing, China [W0153]; CQMU Program for Youth Innovation in Future Medicine [ZYRC2022-04]; CQMU Young Outstanding Scientific and Technological Talents Program [KJQN202300482]; Youth project of science and technology research program of Chongqing Education Commission of China [81700602]; [82070714]"

基金资助正文："This work was supported by grants from the National Natural Science Foundation of China (No: 81700602; 82070714) , the Natural Science Foundation of Chongqing, China (No. CSTB2022NSCQ-MSX0840) , CQMU Program for Youth Innovation in Future Medicine (W0153) , CQMU Young Outstanding Scientific and Technological Talents Program (ZYRC2022-04) , youth project of science and technology research pro-gram of Chongqing Education Commission of China. (KJQN202300482) . After 35-min ischemia and different reperfusion periods with 0 h, 1 h, 3 h, 6 h, 12 h, 24 h, 48 h, and 72 h. Supernatants from right kidney homogenates were used, and total proteins and mRNA were extracted from the right kidney. (A) Concentrations of LXA4 in kidney examined by ELISA. (B) 5-LOX mRNA expressions quantified by RT-qPCR. (C) ALXR mRNA expressions quantified by RT-qPCR. (D) 5-LOX protein expressions by WB. (E) ALXR protein expressions by WB. (F) BUN. (G) Scr. (H) kidney caspase-3 activity. (I) Representative HE-stained renal section from each group (100x, 200x) . (J) Representative renal cell apoptosis from each group identified by TUNEL staining (100x, 200x) . All data are expressed as mean +/- SD (n = 6) , * or #P < 0.05** or ##P < 0.01, ns, not significant, * I/R vs. sham, #LXA4 vs. control."