title: A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis.
abstract: T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25+type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF.
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Moretti
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Renga
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Oikonomou
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Galosi
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Pariano
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Rossana G
authors.initials: RG
authors.lastname: Iannitti
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Borghi
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Puccetti
authors.affiliation: Department of Medical and Biological Science, University of Udine, 33100 Udine, Italy.
authors.forename: Marco
authors.identifier: 0000-0002-1230-2714
authors.initials: M
authors.lastname: De Zuani
authors.affiliation: Department of Medical and Biological Science, University of Udine, 33100 Udine, Italy.
authors.forename: Carlo E
authors.identifier: 0000-0002-4872-6156
authors.initials: CE
authors.lastname: Pucillo
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paolicelli
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Zelante
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, B-1200 Brussels, Belgium.
authors.forename: Jean-Christophe
authors.identifier: 0000-0003-1736-2131
authors.initials: JC
authors.lastname: Renauld
authors.affiliation: Department of Medicine, Section of Pharmacology, University of Perugia, 06132 Perugia, Italy.
authors.forename: Oxana
authors.initials: O
authors.lastname: Bereshchenko
authors.affiliation: Institute of Haematology-CREO (Centro di Ricerche Emato-Oncologiche), Ospedale S. Maria Misericordia, 06132 Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Sportoletti
authors.affiliation: Unit of Endocrinology and Diabetes, Bambino Gesù Children's Hospital, 00165 Rome, Italy.
authors.forename: Vincenzina
authors.initials: V
authors.lastname: Lucidi
authors.affiliation: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, 20122 Milan, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Russo
authors.affiliation: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan, 20122 Milan, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Colombo
authors.affiliation: Bambino Gesù Children's Hospital IRCCS, 00165 Rome, Italy.
authors.forename: Ersilia
authors.initials: E
authors.lastname: Fiscarelli
authors.affiliation: Division of Hygiene and Medical Microbiology, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Lass-Flörl
authors.affiliation: Unit of Endocrinology and Diabetes, Bambino Gesù Children's Hospital, 00165 Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Majo
authors.affiliation: Bambino Gesù Children's Hospital IRCCS, 00165 Rome, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ricciotti
authors.affiliation: CF Centre, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Ellemunter
authors.affiliation: Servizio di Supporto Fibrosi Cistica, Istituto Ospedale G. Tatarella, Foggia, 71042 Cerignola, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ratclif
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Vincenzo Nicola
authors.initials: VN
authors.lastname: Talesa
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Valerio
authors.identifier: 0000-0002-4378-6838
authors.initials: V
authors.lastname: Napolioni
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Luigina
authors.identifier: 0000-0002-1356-525X
authors.initials: L
authors.lastname: Romani
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007223:Infant; D016906:Interleukin-9 / Q000276:immunology; D008168:Lung / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D055815:Young Adult
chemical_list: D016906:Interleukin-9; D019009:Proto-Oncogene Proteins c-kit