title: Reducing hypoxia and inflammation during invasive pulmonary aspergillosis by targeting the Interleukin-1 receptor.
abstract: Hypoxia as a result of pulmonary tissue damage due to unresolved inflammation during invasive pulmonary aspergillosis (IPA) is associated with a poor outcome. Aspergillus fumigatus can exploit the hypoxic microenvironment in the lung, but the inflammatory response required for fungal clearance can become severely disregulated as a result of hypoxia. Since severe inflammation can be detrimental to the host, we investigated whether targeting the interleukin IL-1 pathway could reduce inflammation and tissue hypoxia, improving the outcome of IPA. The interplay between hypoxia and inflammation was investigated by in vivo imaging of hypoxia and measurement of cytokines in the lungs in a model of corticosteroid immunocompromised and in Cxcr2 deficient mice. Severe hypoxia was observed following Aspergillus infection in both models and correlated with development of pulmonary inflammation and expression of hypoxia specific transcripts. Treatment with IL-1 receptor antagonist reduced hypoxia and slightly, but significantly reduced mortality in immunosuppressed mice, but was unable to reduce hypoxia in Cxcr2(-/-) mice. Our data provides evidence that the inflammatory response during invasive pulmonary aspergillosis, and in particular the IL-1 axis, drives the development of hypoxia. Targeting the inflammatory IL-1 response could be used as a potential immunomodulatory therapy to improve the outcome of aspergillosis.
authors.affiliation: Unité de recherche Cytokines &Inflammation, Institut Pasteur, Paris.|Department of Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Gresnigt
authors.affiliation: PFID, Bioaster, Institut Pasteur, Paris France.
authors.forename: Abdessalem
authors.initials: A
authors.lastname: Rekiki
authors.affiliation: Unité de recherche Cytokines &Inflammation, Institut Pasteur, Paris.
authors.forename: Orhan
authors.initials: O
authors.lastname: Rasid
authors.affiliation: Fungal Genetics and Biology, School of Life Sciences, University of Nottingham, UK.
authors.forename: Amélie
authors.initials: A
authors.lastname: Savers
authors.affiliation: Unité Histopathologie Humaine et Modèles Animaux, Institut Pasteur, Paris France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Jouvion
authors.affiliation: Paris-Descartes University, Faculty of Medicine, APHP, European Georges Pompidou Hospital, Parasitology-Mycology Unit, Microbiology department, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Dannaoui
authors.affiliation: INSERM UMR S1163 Institut Imagine, Laboratoire d'Immunité Intestinale, Paris France.
authors.forename: Marianna
authors.initials: M
authors.lastname: Parlato
authors.affiliation: Unité de recherche Cytokines &Inflammation, Institut Pasteur, Paris.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fitting
authors.affiliation: Fungal Genetics and Biology, School of Life Sciences, University of Nottingham, UK.
authors.forename: Matthias
authors.initials: M
authors.lastname: Brock
authors.affiliation: Unité de recherche Cytokines &Inflammation, Institut Pasteur, Paris.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Cavaillon
authors.affiliation: Department of Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Unité de recherche Cytokines &Inflammation, Institut Pasteur, Paris.
authors.forename: Oumaïma
authors.initials: O
authors.lastname: Ibrahim-Granet
mesh_terms: D000305:Adrenal Cortex Hormones / Q000009:adverse effects*; D000818:Animals; D000071231:Carbonic Anhydrase IX / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D016867:Immunocompromised Host; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage* / Q000494:pharmacology; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D051379:Mice; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D023063:Receptors, Interleukin-8B / Q000172:deficiency* / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1; D023063:Receptors, Interleukin-8B; D000071231:Carbonic Anhydrase IX; C492796:Car9 protein, mouse