Constitutive immune activity promotes JNK- and FoxO-dependent remodeling of Drosophila airways.

Christina Wagner,Michael Wegmann,Ulrich M Zissler,Holger Heine,Christina Vock,Neil Silverman,Heinz Fehrenbach,Thomas Roeder,Judith Bossen,Marcus Thiedmann,Kerstin Isermann,Peter König,Harald Renz,Holger Garn,Ahmed Abdelsadik,Mario Pieper,Mirjam Knop,Karin Uliczka,Christine Fink,Xiao Niu,Claus Vogelmeier ,Andreas Rembert Koczulla ,Carsten B Schmidt‐Weber ,Petra Ina Pfefferle

doi:10.1016/j.celrep.2021.108956

Abstract

Extensive remodeling of the airways is a major characteristic of chronic inflammatory lung diseases such as asthma or chronic obstructive pulmonary disease (COPD). To elucidate the importance of a deregulated immune response in the airways for remodeling processes, we established a matching Drosophila model. Here, triggering the Imd (immune deficiency) pathway in tracheal cells induced organ-wide remodeling. This structural remodeling comprises disorganization of epithelial structures and comprehensive epithelial thickening. We show that these structural changes do not depend on the Imd pathway's canonical branch terminating on nuclear factor κB (NF-κB) activation. Instead, activation of a different segment of the Imd pathway that branches off downstream of Tak1 and comprises activation of c-Jun N-terminal kinase (JNK) and forkhead transcription factor of the O subgroup (FoxO) signaling is necessary and sufficient to mediate the observed structural changes of the airways. Our findings imply that targeting JNK and FoxO signaling in the airways could be a promising strategy to interfere with disease-associated airway remodeling processes.

Highlights

Airway epithelial cells constitute the first line of defense against airborne pathogens but are pivotal for maintaining the lung’s structural integrity and immune homeostasis (Lambrecht and Hammad, 2012; Proud and Leigh, 2011; Whitsett and Alenghat, 2015)
Constitutive immune deficiency (Imd) activation in the airway epithelium induces a strong antimicrobial response Taking advantage of its simple airway structure and the unique and highly versatile toolbox available for Drosophila (Kallsen et al, 2015; Wagner et al, 2008), we studied the outcome of constitutively activated innate immune signaling in airway epithelial cells
Constitutive Imd activation leads to thickening of the airway epithelium at all life stages Beside expression of antimicrobial peptides, the most intriguing phenotype observed in response to persistent Imd activation was thickening of the epithelial layer

Summary

Introduction

Airway epithelial cells constitute the first line of defense against airborne pathogens but are pivotal for maintaining the lung’s structural integrity and immune homeostasis (Lambrecht and Hammad, 2012; Proud and Leigh, 2011; Whitsett and Alenghat, 2015). COPD (chronic obstructive pulmonary disease), and cystic and pulmonary fibrosis, are associated with inflammation and structural remodeling (Adam et al, 2015; Camelo et al, 2014; Hiemstra et al, 2015; Holgate, 2007a; Whitsett and Alenghat, 2015). Deregulated epithelial immune homeostasis appears to be involved in most of these diseases (Proud and Leigh, 2011; Van Eerdewegh et al, 2002; Wark et al, 2005). NF-kB signaling in airway epithelial cells regulates the expression of proinflammatory cytokines and antimicrobial peptides but has been shown to be involved in structural remodeling processes of the entire lung, including goblet cell hyperplasia and dedifferentiation of epithelial cells (Broide et al, 2005; Pantano et al, 2008)

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