title: Axl receptor blockade protects from invasive pulmonary aspergillosis in mice.
abstract: Aspergillus fumigatus is a sporulating fungus found ubiquitously in the environment, which is quickly contained in the immunocompetent host but can cause lethal invasive aspergillosis in the immunocompromised host. We have recently demonstrated that Axl (one member of the Tyro3, Axl, Mertk receptor family) is a key regulator of antiviral immune responses in the lung. In this study, we investigated the role of Axl in antifungal immunity in a model of invasive pulmonary aspergillosis (IPA). In this model, Aspergillus fumigatus conidia were administered into the lungs of neutrophil-depleted mice, and the mice were monitored for survival, lung inflammatory response, and fungal clearance. The lethal effect of IPA was significantly reduced in anti-Axl mAb-treated mice compared with IgG control-treated mice. Targeting Axl significantly inhibited pulmonary inflammation, including the expression of IL-1β, IL-6, TNF-α, and chitinase-like proteins in whole lung. Further, anti-Axl mAb treatment significantly increased M1 macrophages that highly expressed inducible NO synthase and decreased M2 macrophages that expressed Arginase 1 and were found in inflammatory zone protein (Fizz1). More importantly, anti-Axl mAb treatment significantly increased the number of IFN-γ-producing T cells and NK cells compared with the IgG control group during IPA. Together, our results demonstrate that the Axl mAb treatment is protective during invasive aspergillosis in neutropenic mice. Collectively, these data suggest a potential deleterious role for Axl during primary immune responses directed against A. fumigatus and novel therapeutic strategy for IPA.
authors.affiliation: Immunology Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and tshibata@nih.go.jp Cory.Hogaboam@cshs.org.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: David M
authors.initials: DM
authors.lastname: Habiel
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Ana Lucia
authors.initials: AL
authors.lastname: Coelho
authors.affiliation: Immunology Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and tshibata@nih.go.jp Cory.Hogaboam@cshs.org.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001232:Aspergillus fumigatus / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000473:pathology; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; C413576:Retnla protein, mouse; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase