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
{"title":"Treatment with lipoxin A<sub>4</sub> improves influenza A infection outcome, induces macrophage reprogramming, anti-inflammatory and pro-resolutive responses.","authors":"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","doi":"10.1007/s00011-024-01939-9","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Objective: </strong>Here, we evaluated whether a synthetic lipoxin mimetic, designated AT-01-KG, would improve the course of influenza A infection in a murine model.</p><p><strong>Method: </strong>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.</p><p><strong>Results: </strong>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 <sup>-/-</sup> animals. In mice treated with LXA<sub>4</sub> (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.</p><p><strong>Conclusion: </strong>Therefore, treatment with a lipoxin A<sub>4</sub> 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.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":" ","pages":"1903-1918"},"PeriodicalIF":4.8000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Inflammation Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00011-024-01939-9","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/30 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
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.