Notch2 is required for inflammatory cytokine-driven goblet cell metaplasia in the lung

Henry Danahay; Angelica D Pessotti; Julie Coote; Brooke E Montgomery; Donghui Xia; Aaron Wilson; Haidi Yang; Zhao Wang; Luke Bevan; Chris Thomas; Stephanie Petit; Anne London; Peter LeMotte; Arno Doelemeyer; Germán L Vélez-Reyes; Paula Bernasconi; Christy J Fryer; Matt Edwards; Paola Capodieci; Amy Chen; Marc Hild; Aron B Jaffe

doi:10.1016/j.celrep.2014.12.017

Notch2 is required for inflammatory cytokine-driven goblet cell metaplasia in the lung

Cell Rep. 2015 Jan 13;10(2):239-52. doi: 10.1016/j.celrep.2014.12.017. Epub 2014 Dec 31.

Authors

Henry Danahay¹, Angelica D Pessotti², Julie Coote³, Brooke E Montgomery², Donghui Xia², Aaron Wilson², Haidi Yang², Zhao Wang², Luke Bevan³, Chris Thomas², Stephanie Petit², Anne London⁴, Peter LeMotte⁴, Arno Doelemeyer⁵, Germán L Vélez-Reyes², Paula Bernasconi², Christy J Fryer², Matt Edwards³, Paola Capodieci², Amy Chen², Marc Hild², Aron B Jaffe⁶

Affiliations

¹ Respiratory Disease Area, Novartis Institutes for BioMedical Research, Horsham RH12 5AB, UK. Electronic address: h.danahay@sussex.ac.uk.
² Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
³ Respiratory Disease Area, Novartis Institutes for BioMedical Research, Horsham RH12 5AB, UK.
⁴ Novartis Biologics Center, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
⁵ Discovery and Investigative Pathology, Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
⁶ Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: aron.jaffe@novartis.com.

PMID: 25558064
DOI: 10.1016/j.celrep.2014.12.017

Abstract

The balance and distribution of epithelial cell types is required to maintain tissue homeostasis. A hallmark of airway diseases is epithelial remodeling, leading to increased goblet cell numbers and an overproduction of mucus. In the conducting airway, basal cells act as progenitors for both secretory and ciliated cells. To identify mechanisms regulating basal cell fate, we developed a screenable 3D culture system of airway epithelial morphogenesis. We performed a high-throughput screen using a collection of secreted proteins and identified inflammatory cytokines that specifically biased basal cell differentiation toward a goblet cell fate, culminating in enhanced mucus production. We also demonstrate a specific requirement for Notch2 in cytokine-induced goblet cell metaplasia in vitro and in vivo. We conclude that inhibition of Notch2 prevents goblet cell metaplasia induced by a broad range of stimuli and propose Notch2 neutralization as a therapeutic strategy for preventing goblet cell metaplasia in airway diseases.

MeSH terms

Animals
Cell Culture Techniques
Cell Differentiation / drug effects
Cells, Cultured
Cytokines / genetics
Cytokines / metabolism
Cytokines / pharmacology*
Disease Models, Animal
Epithelial Cells / cytology
Epithelial Cells / drug effects
Epithelial Cells / metabolism
Female
Goblet Cells / cytology
Goblet Cells / drug effects*
Goblet Cells / metabolism
Hepatocyte Nuclear Factor 3-gamma / genetics
Hepatocyte Nuclear Factor 3-gamma / metabolism
Humans
Interleukin-13 / genetics
Interleukin-13 / metabolism
Interleukin-13 / pharmacology
Interleukin-17 / genetics
Interleukin-17 / metabolism
Interleukin-17 / pharmacology
Lung / metabolism
Lung / pathology*
Metaplasia
Mice
Mice, Inbred BALB C
Mucin 5AC / genetics
Mucin 5AC / metabolism
Mucin-5B / genetics
Mucin-5B / metabolism
Receptor, Notch2 / metabolism*
Recombinant Proteins / biosynthesis
Recombinant Proteins / genetics
Recombinant Proteins / pharmacology

Substances

Cytokines
FOXA3 protein, human
Interleukin-13
Interleukin-17
MUC5AC protein, human
MUC5B protein, human
Mucin 5AC
Mucin-5B
NOTCH2 protein, human
Receptor, Notch2
Recombinant Proteins
Hepatocyte Nuclear Factor 3-gamma