Valdirene S Muniz1, Juliana C Silva2, Yasmim A V Braga2, Rossana C N Melo3, Shigeharu Ueki4, Masahide Takeda4, Akira Hebisawa5, Koichiro Asano6, Rodrigo T Figueiredo7, Josiane S Neves8. 1. Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 2. Institute of Biomedical Sciences/Institute of Microbiology Paulo de Góes, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 3. Laboratory of Cellular Biology, Department of Biology, Institute of Biological Sciences, Federal University of Juiz de Fora, Juiz de Fora, Brazil. 4. Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan. 5. Clinical Research Center and Pathology Division, National Hospital Organization Tokyo National Hospital, Tokyo, Japan. 6. Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Kanagawa, Japan. 7. Institute of Biomedical Sciences/Unit of Xerem, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 8. Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: jneves@icb.ufrj.br.
Abstract
BACKGROUND: Eosinophils mediate the immune response in different infectious conditions. The release of extracellular DNA traps (ETs) by leukocytes has been described as an innate immune response mechanism that is relevant in many disorders including fungal diseases. Different stimuli induce the release of human eosinophil ETs (EETs). Aspergillus fumigatus is an opportunistic fungus that may cause eosinophilic allergic bronchopulmonary aspergillosis (ABPA). It has been reported that eosinophils are important to the clearance of A fumigatus in infected mice lungs. However, the immunological mechanisms that underlie the molecular interactions between A fumigatus and eosinophils are poorly understood. OBJECTIVE: Here, we investigated the presence of EETs in the bronchial mucus plugs of patients with ABPA. We also determined whether A fumigatus induced the release of human eosinophil EETs in vitro. METHODS: Mucus samples of patients with ABPA were analyzed by light and confocal fluorescence microscopy. The release of EETs by human blood eosinophils was evaluated using different pharmacological tools and neutralizing antibodies by fluorescence microscopy and a fluorimetric method. RESULTS: We identified abundant nuclear histone-bearing EETs in the bronchial secretions obtained from patients with ABPA. In vitro, we demonstrated that A fumigatus induces the release of EETs through a mechanism independent of reactive oxygen species but associated with eosinophil death, histone citrullination, CD11b, and the Syk tyrosine kinase pathway. EETs lack the killing or fungistatic activities against A fumigatus. CONCLUSIONS: Our findings may contribute to the understanding of how eosinophils recognize and act as immune cells in response to A fumigatus, which may lead to novel insights regarding the treatment of patients with ABPA.
BACKGROUND: Eosinophils mediate the immune response in different infectious conditions. The release of extracellular DNA traps (ETs) by leukocytes has been described as an innate immune response mechanism that is relevant in many disorders including fungal diseases. Different stimuli induce the release of human eosinophil ETs (EETs). Aspergillus fumigatus is an opportunistic fungus that may cause eosinophilic allergic bronchopulmonary aspergillosis (ABPA). It has been reported that eosinophils are important to the clearance of A fumigatus in infected mice lungs. However, the immunological mechanisms that underlie the molecular interactions between A fumigatus and eosinophils are poorly understood. OBJECTIVE: Here, we investigated the presence of EETs in the bronchial mucus plugs of patients with ABPA. We also determined whether A fumigatus induced the release of human eosinophil EETs in vitro. METHODS: Mucus samples of patients with ABPA were analyzed by light and confocal fluorescence microscopy. The release of EETs by human blood eosinophils was evaluated using different pharmacological tools and neutralizing antibodies by fluorescence microscopy and a fluorimetric method. RESULTS: We identified abundant nuclear histone-bearing EETs in the bronchial secretions obtained from patients with ABPA. In vitro, we demonstrated that A fumigatus induces the release of EETs through a mechanism independent of reactive oxygen species but associated with eosinophil death, histone citrullination, CD11b, and the Syk tyrosine kinase pathway. EETs lack the killing or fungistatic activities against A fumigatus. CONCLUSIONS: Our findings may contribute to the understanding of how eosinophils recognize and act as immune cells in response to A fumigatus, which may lead to novel insights regarding the treatment of patients with ABPA.
Authors: Stephane Esnault; Jonathan P Leet; Mats W Johansson; Karina T Barretto; Paul S Fichtinger; Frances J Fogerty; Ksenija Bernau; Sameer K Mathur; Deane F Mosher; Nathan Sandbo; Nizar N Jarjour Journal: Clin Exp Allergy Date: 2019-12-09 Impact factor: 5.018
Authors: Pedro H Gazzinelli-Guimaraes; Rafael de Queiroz Prado; Alessandra Ricciardi; Sandra Bonne-Année; Joshua Sciurba; Erik P Karmele; Ricardo T Fujiwara; Thomas B Nutman Journal: J Clin Invest Date: 2019-08-05 Impact factor: 14.808
Authors: Hans-Uwe Simon; Shida Yousefi; Nina Germic; Isabelle C Arnold; Angela Haczku; Alexander V Karaulov; Dagmar Simon; Helene F Rosenberg Journal: Int Arch Allergy Immunol Date: 2019-11-29 Impact factor: 2.749