title: Effects of Aspergillus fumigatus gliotoxin and methylprednisolone on human neutrophils: implications for the pathogenesis of invasive aspergillosis.
abstract: Aspergillus fumigatus (AF) is a ubiquitous mold and the most common cause of invasive aspergillosis (IA) in immunocompromised patients. In stem cell transplant recipients, IA now occurs most frequently in the setting of therapy with corticosteroids, including methylprednisolone (MP). We showed previously that gliotoxin (GT), an AF-derived mycotoxin, induces apoptosis in monocytes and dendritic cells, resulting in the suppression of AF-specific T cell responses. We examined the ability of GT to induce apoptosis in polymorphonuclear leukocytes (PMN) and assessed GT effects on important neutrophil functions, including phagocytic function, degranulation, myeloperoxidase activity, and the production of reactive oxygen species (ROS). In contrast to its effects on monocytes, PMN remained resistant to GT-mediated apoptosis. Although many essential neutrophil functions were unaffected, GT inhibited phagocytosis and also induced a decrease in ROS generation by PMN. In contrast, MP therapy potentiated ROS production, suggesting a mechanism that may facilitate tissue injury in IA. Distinct from its effects on untreated PMN, GT augmented ROS production in MP-treated PMN. Our results suggest that although GT may suppress the adaptive immune response, GT may also serve to increase PMN-mediated inflammation, which is likely to play an important role in tissue destruction in the setting of IA.
authors.affiliation: Department of Oncology, Transplant and Advances in Medicine, University of Pisa, Italy. orci@sssup.it
authors.forename: Enrico
authors.initials: E
authors.lastname: Orciuolo
authors.forename: Marta
authors.initials: M
authors.lastname: Stanzani
authors.forename: Martina
authors.initials: M
authors.lastname: Canestraro
authors.forename: Sara
authors.initials: S
authors.lastname: Galimberti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Carulli
authors.forename: Russell
authors.initials: R
authors.lastname: Lewis
authors.forename: Mario
authors.initials: M
authors.lastname: Petrini
authors.forename: Krishna V
authors.initials: KV
authors.lastname: Komanduri
mesh_terms: D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001228:Aspergillosis / Q000188:drug therapy / Q000276:immunology*; D001232:Aspergillus fumigatus / Q000276:immunology / Q000472:pathogenicity*; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005912:Gliotoxin / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D016867:Immunocompromised Host / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology; D008775:Methylprednisolone / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D009195:Peroxidase / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology; D033581:Stem Cell Transplantation / Q000009:adverse effects
chemical_list: D000893:Anti-Inflammatory Agents; D017382:Reactive Oxygen Species; D005912:Gliotoxin; D009195:Peroxidase; D008775:Methylprednisolone