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

• Published in: Clinical immunology (Orlando, Fla.) Vol. 261; p. 110167
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2024
• Subjects: IRAK-M; IRG1; Ischemia/reperfusion; Lipoxin A4; Nrf2; Scr; CXCL1; I/R; MyD88; GPx 2; IRG1; NF-κB; TUNEL; SDH; KEGG; 5-LOX; RT-qPCR; MAPKs; IRAK-M; PBS; IL; Lipoxin A4; TBS; GSEA; PVDF; TIRAP; IRAK; SDS-PAGE; TRAF6; ROS; CAT; LXA4; GAPDH; ELISA; DHE; UPLC-MS; PRRs; HO-1; Ischemia/reperfusion; DAMPs; SD; 8-OHG; TAK1; Nrf2; CCL2; BUN; TLR; AKI; 8-OHdG; NQO-1; KO; GO; SOD; TNF-α; IRI-AKI; HE
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2024.110167

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. [Display omitted] •LXA4 is quickly induced and protects against kidney ischemia/reperfusion(I/R) injury.•LXA4 inhibits inflammatory response by promoting IRAK-M to inhibit TLR4 pathway.•LXA4 inhibits oxidative stress via promoting IRG1/Nrf2 pathway.•LXA4 is a pharmacological candidate for treatment and prevention of kidney I/R injury.