Liraglutide alleviates ferroptosis in renal ischemia reperfusion injury via inhibiting macrophage extracellular trap formation.

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2024-12-05 Epub Date: 2024-09-27 DOI:10.1016/j.intimp.2024.113258

Zejia Sun, Feilong Zhang, Zihao Gao, Jiyue Wu, Qing Bi, Xiang Zheng, Jiandong Zhang, Peng Cao, Wei Wang

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Abstract

Background and purpose: Renal transplantation and other conditions with transiently reduced blood flow is major cause of renal ischemia/reperfusion injury (RIRI), a therapeutic challenge clinically. This study investigated the role of liraglutide in ferroptosis-associated RIRI via macrophage extracellular traps (METs).

Methods: Animal model with RIRI was established in C57BL/6J mice. A total of 72 C57BL/6J mice were used with 8 mice per group. Primary tubular epithelium was co-culture with RAW264.7 under hypoxia/reoxygenation (H/R) condition to mimic in vitro. Liraglutide was administrated into mice and cells. Extracellular DNA, neutrophil elastase and myeloperoxidase in serum and supernatant of cell medium were collected for measuring METs. F4/80 and citH3 were labeled to show METs.

Results: Liraglutide relieved RIRI and ferroptosis in vivo, and inhibited renal I/R-induced METs both in vivo and in vitro. F4/80 and citrullinated histone H3 (citH3) were highly co-localized after RIRI. Liraglutide attenuated the co-localization of citH3 and F4/80. Expressions of M2 markers were enhanced whereas these of M1 markers suppressed during liraglutide treatment in RIRI. Phosphorylation of signal transducer and activator of transcription (STAT)1, 3 and 6 were increased in RIRI mice and H/R-induced RAW264.7. However, liraglutide decreased phosphorylation of STAT1 and increased phosphorylation of STAT3 and STAT6. STAT3/6 inhibition reversed liraglutide-inhibited M1 polarization, extracellular traps and ferroptosis.

Conclusion: Liraglutide inhibited ferroptosis-induced renal dysfunction since it skewed macrophage polarization into M2 phenotype that interfered the formation of extracellular traps based on STAT3/6 pathway during RIRI. Liraglutide was proposed to be used for RIRI clinical treatment.

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利拉鲁肽通过抑制巨噬细胞胞外陷阱的形成减轻肾缺血再灌注损伤中的铁蛋白沉积。

背景和目的：肾移植和其他情况下的短暂血流减少是肾缺血/再灌注损伤（RIRI）的主要原因，也是临床治疗的难题。本研究探讨了利拉鲁肽通过巨噬细胞胞外捕获器（METs）在铁蛋白沉积相关RIRI中的作用：方法：在C57BL/6J小鼠中建立RIRI动物模型。共使用 72 只 C57BL/6J 小鼠，每组 8 只。原代肾小管上皮细胞与 RAW264.7 在缺氧/复氧（H/R）条件下共同培养，以模拟体外培养。给小鼠和细胞注射利拉鲁肽。收集血清和细胞培养基上清液中的细胞外 DNA、中性粒细胞弹性蛋白酶和髓过氧化物酶，用于测量 METs。F4/80和citH3被标记为METs：结果：利拉鲁肽缓解了体内RIRI和铁变态反应，并抑制了体内和体外肾脏I/R诱导的MET。RIRI后，F4/80和瓜氨酸组蛋白H3（citH3）高度共定位。利拉鲁肽减弱了 citH3 和 F4/80 的共定位。在利拉鲁肽治疗 RIRI 期间，M2 标志物的表达增强，而 M1 标志物的表达减弱。在 RIRI 小鼠和 H/R 诱导的 RAW264.7 中，信号转导和转录激活因子（STAT）1、3 和 6 的磷酸化增加。然而，利拉鲁肽降低了STAT1的磷酸化，增加了STAT3和STAT6的磷酸化。STAT3/6抑制逆转了利拉鲁肽抑制的M1极化、细胞外陷阱和铁绒毛变性：结论：利拉鲁肽抑制了铁蛋白沉积诱导的肾功能障碍，因为它使巨噬细胞极化为M2表型，从而干扰了RIRI期间基于STAT3/6途径的细胞外陷阱的形成。建议将利拉鲁肽用于RIRI的临床治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.