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.

中文翻译：

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LXA4通过促进IRG1/Nrf2和IRAK-M-TRAF6信号通路保护小鼠免受肾缺血/再灌注损伤

过度的炎症反应和氧化应激增加在缺血/再灌注（I/R）诱导的急性肾损伤（IRI-AKI）的病理生理学中发挥着重要作用。新的证据表明，脂氧素 A4 (LXA4) 作为炎症的内源性负调节剂，可以改善多种缺血再灌注损伤。然而，LXA4 对 IRI-AKI 的机制和影响仍不清楚。在本研究中，使用双侧肾 I/R 小鼠模型来评估 LXA4 在野生型、IRG1 敲除和 IRAK-M 敲除小鼠中的作用。我们的结果表明，LXA4 以及 5-LOX 和 ALXR 很快被诱导，并随后因肾缺血再灌注而降低。LXA4预处理可改善肾缺血再灌注引起的肾功能损伤和肾损伤，并抑制小鼠肾脏的炎症反应和氧化应激。值得注意的是，LXA4 抑制 I/R 诱导的 TLR4 信号通路激活，包括降低 TAK1、p36 和 p65 的磷酸化，但不影响 TLR4 和 p-IRAK-1。转录组测序数据和免疫印迹分析表明，先天免疫信号分子白细胞介素1受体相关激酶M（IRAK-M）和免疫反应基因1（IRG1）可能是LXA4的关键靶点。此外，IRG1 或 IRAK-M 的敲除消除了 LXA4 对 IRI-AKI 的有益作用。此外，IRG1缺陷逆转了LXA4对IRAK-M的上调，而IRAK-M敲除对IRG1表达没有影响，表明IRAK-M是IRG1的下游分子。从机制上讲，我们发现LXA4促进的IRG1-衣康酸不仅增强Nrf2激活并增加HO-1和NQO1，而且上调IRAK-M，IRAK-M通过与IRAK-1竞争与TRAF6相互作用，导致TLR4下游信号失活。 IRI-AKI。这些数据表明，LXA4 通过促进 IRG1/Itaconate-Nrf2 和 IRAK-M-TRAF6 信号通路来预防 IRI-AKI，为预防和治疗 IRI-AKI 的新策略提供了理论依据。