A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis

Silvia Moretti, Giorgia Renga, Vasilis Oikonomou, Claudia Galosi, Marilena Pariano, Rossana G. Iannitti, Monica Borghi, Matteo Puccetti, Marco De Zuani, Carlo E. Pucillo, Giuseppe Paolicelli, Teresa Zelante, Jean-Christophe Renauld, Oxana Bereshchenko, Paolo Sportoletti, Vincenzina Lucidi, Maria Chiara Russo, Carla Colombo, Ersilia Fiscarelli, Cornelia Lass-Flörl, Fabio Majo, Gabriella Ricciotti, Helmut Ellemunter, Luigi Ratclif, Vincenzo Nicola Talesa, Valerio Napolioni and Luigina Romani ()
Additional contact information
Silvia Moretti: University of Perugia
Giorgia Renga: University of Perugia
Vasilis Oikonomou: University of Perugia
Claudia Galosi: University of Perugia
Marilena Pariano: University of Perugia
Rossana G. Iannitti: University of Perugia
Monica Borghi: University of Perugia
Matteo Puccetti: University of Perugia
Marco De Zuani: University of Udine
Carlo E. Pucillo: University of Udine
Giuseppe Paolicelli: University of Perugia
Teresa Zelante: University of Perugia
Jean-Christophe Renauld: Ludwig Institute for Cancer Research, Brussels Branch
Oxana Bereshchenko: Section of Pharmacology, University of Perugia
Paolo Sportoletti: Institute of Haematology-CREO (Centro di Ricerche Emato-Oncologiche), Ospedale S. Maria Misericordia
Vincenzina Lucidi: Unit of Endocrinology and Diabetes, Bambino Gesù Children's Hospital
Maria Chiara Russo: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan
Carla Colombo: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan
Ersilia Fiscarelli: Bambino Gesù Children's Hospital IRCCS
Cornelia Lass-Flörl: Innsbruck Medical University
Fabio Majo: Unit of Endocrinology and Diabetes, Bambino Gesù Children's Hospital
Gabriella Ricciotti: Bambino Gesù Children's Hospital IRCCS
Helmut Ellemunter: CF Centre, Medical University Innsbruck
Luigi Ratclif: Servizio di Supporto Fibrosi Cistica, Istituto Ospedale G. Tatarella
Vincenzo Nicola Talesa: University of Perugia
Valerio Napolioni: University of Perugia
Luigina Romani: University of Perugia

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14017

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