Treatment with lipoxin A4 improves influenza A infection outcome, induces macrophage reprogramming, anti-inflammatory and pro-resolutive responses.

IF 4.8 3区 医学 Q2 CELL BIOLOGY Inflammation Research Pub Date : 2024-11-01 Epub Date: 2024-08-30 DOI:10.1007/s00011-024-01939-9
Flavia Rago, Eliza Mathias Melo, Leigh M Miller, Alexis M Duray, Franciel Batista Felix, Juliana Priscila Vago, Ana Paula de Faria Gonçalves, Ana Luiza Pessoa Mendonça Angelo, Geovanni D Cassali, Monica de Gaetano, Eoin Brennan, Benjamin Owen, Patrick Guiry, Catherine Godson, John F Alcorn, Mauro Martins Teixeira
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Abstract

Introduction: Influenza A is a virus from the Orthomixoviridae family responsible for high lethality rates and morbidity, despite clinically proven vaccination strategies and some anti-viral therapies. The eicosanoid Lipoxin A4 (LXA4) promotes the resolution of inflammation by decreasing cell recruitment and pro-inflammatory cytokines release, but also for inducing activation of apoptosis, efferocytosis, and macrophage reprogramming.

Objective: Here, we evaluated whether a synthetic lipoxin mimetic, designated AT-01-KG, would improve the course of influenza A infection in a murine model.

Method: Mice were infected with influenza A/H1N1 and treated with AT-01-KG (1.7 μg/kg/day, i.p.) at day 3 post-infection.

Results: AT-01-KG attenuated mortality, reducing leukocyte infiltration and lung damage at day 5 and day 7 post-infection. AT-01-KG is a Formyl Peptide Receptor 2 (designated FPR2/3 in mice) agonist, and the protective responses were not observed in fpr2/3 -/- animals. In mice treated with LXA4 (50 μg/kg/day, i.p., days 3-6 post-infection), at day 7, macrophage reprogramming was observed, as seen by a decrease in classically activated macrophages and an increase in alternatively activated macrophages in the lungs. Furthermore, the number of apoptotic cells and cells undergoing efferocytosis was increased in the lavage of treated mice. Treatment also modulated the adaptive immune response, increasing the number of T helper 2 cells (Th2) and regulatory T (Tregs) cells in the lungs of the treated mice.

Conclusion: Therefore, treatment with a lipoxin A4 analog was beneficial in a model of influenza A infection in mice. The drug decreased inflammation and promoted resolution and beneficial immune responses, suggesting it may be useful in patients with severe influenza.

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用脂毒素 A4 治疗可改善甲型流感感染结果,诱导巨噬细胞重编程、抗炎和促复原反应。
导言:甲型流感是一种来自正粘病毒科的病毒,尽管有临床验证的疫苗接种策略和一些抗病毒疗法,但其致死率和发病率仍然很高。类二十碳素脂氧素 A4(LXA4)通过减少细胞募集和促炎细胞因子的释放来促进炎症的缓解,同时还能诱导激活细胞凋亡、排泄和巨噬细胞重编程:方法:小鼠感染甲型 H1N1 流感,并在感染后第 3 天接受 AT-01-KG(1.7 μg/kg/天,静脉注射)治疗:结果:AT-01-KG可降低死亡率,减少感染后第5天和第7天的白细胞浸润和肺损伤。AT-01-KG 是一种甲酰肽受体 2(小鼠称为 FPR2/3)激动剂,在 fpr2/3 -/- 动物中未观察到保护性反应。用 LXA4(50 μg/kg/天,肌注,感染后第 3-6 天)治疗的小鼠,在第 7 天观察到巨噬细胞重编程,表现为肺部经典活化巨噬细胞减少,替代活化巨噬细胞增加。此外,经处理的小鼠灌洗液中的凋亡细胞和流出细胞数量增加。治疗还调节了适应性免疫反应,增加了治疗小鼠肺中 T 辅助 2 细胞(Th2)和调节性 T 细胞(Tregs)的数量:因此,用脂毒素 A4 类似物治疗甲型流感感染模型小鼠是有益的。结论:因此,用脂毒素 A4 类似物治疗甲型流感感染模型小鼠是有益的,这种药物能减轻炎症,促进炎症消退和有益的免疫反应,这表明它可能对重症流感患者有用。
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来源期刊
Inflammation Research
Inflammation Research 医学-免疫学
CiteScore
9.90
自引率
1.50%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.
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