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

Bibliographische Detailangaben
Veröffentlicht in:	Clinical immunology (Orlando, Fla.). - 1999. - 261(2024) vom: 05. Apr., Seite 110167
1. Verfasser:	Tie, Hongtao (VerfasserIn)
Weitere Verfasser:	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
Format:	Online-Aufsatz
Sprache:	English
Veröffentlicht:	2024
Zugriff auf das übergeordnete Werk:	Clinical immunology (Orlando, Fla.)
Schlagworte:	Journal Article Research Support, Non-U.S. Gov't IRAK-M IRG1 Ischemia/reperfusion Lipoxin A4 Nrf2 lipoxin A4 itaconic acid Q4516562YH mehr... NF-E2-Related Factor 2 TNF Receptor-Associated Factor 6 Toll-Like Receptor 4 Interleukin-1 Receptor-Associated Kinases EC 2.7.11.1 Succinates Lipoxins

Beschreibung
Zusammenfassung:	Copyright © 2024 Elsevier Inc. All rights reserved. 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
Beschreibung:	Date Completed 18.03.2024 Date Revised 10.04.2024 published: Print-Electronic Citation Status MEDLINE
ISSN:	1521-7035
DOI:	10.1016/j.clim.2024.110167