Journal Article

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

Romani, Luigina, Borghi, Monica, De Zuani, Marco, Bereshchenko, Oxana, Moretti, Silvia, Fiscarelli, Ersilia, Majo, Fabio, Renauld, Jean-Christophe, Colombo, Carla, Iannitti, Rossana G., Paolicelli, Giuseppe, Lucidi, Vincenzina, Ratclif, Luigi, Oikonomou, Vasilis, Napolioni, Valerio, Ellemunter, Helmut, Galosi, Claudia, Ricciotti, Gabriella, Sportoletti, Paolo, Puccetti, Matteo, Talesa, Vincenzo Nicola, Pucillo, Carlo E., Lass-Flörl, Cornelia, Pariano, Marilena, Zelante, Teresa, Russo, Maria Chiara, Renga, Giorgia

2017

Overview

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. In patients with cystic fibrosis, IL-9 signalling is increased. The authors describe an inflammatory loop in which IL-9 produced by Th9 cells drives mast cells to produce IL-2, resulting in ILC2 cell activation, and show inhibition of this loop with blocking antibodies to IL-9 in a mouse model of pulmonary infection.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/21 / 13/31 / 13/51 / 14/63 / 38/77 / 631/250/256 / 631/45/127/1213 / 64/60 / 692/699/1785/4039 / Adolescent / Adult / Allergies / Animals / Child / Child, Preschool / Cystic fibrosis / Cystic Fibrosis - genetics / Cystic Fibrosis - immunology / Cytokines / Female / Humanities and Social Sciences / Humans / Immunity, Innate / Infant / Infections / Interleukin-9 - immunology / Lung - immunology / Lungs / Lymphocytes - immunology / Male / Mast Cells - immunology / Mice / Mice, Inbred C57BL / Middle Aged / multidisciplinary / Proto-Oncogene Proteins c-kit - immunology / Science / Science (multidisciplinary) / T-Lymphocytes, Helper-Inducer - immunology / Young Adult