Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation.

Atiqur Rahman,Caroline Tabor,David Sammut,Abigail E Reese,Nika Khoshaein,Claudia Tulotta,Ian Sabroe,William J Zuercher ,Moira K B Whyte ,Annemarie H Meijer ,A A Roger Thompson ,Kimberly Herman ,Stephen A Renshaw ,David H Dockrell ,Julien Rougeot ,Katherine M Henry ,Hannah M Isles ,Katie Higgins ,Caroline O.s Savage ,Lynne R Prince

doi:10.7554/elife.50990

Abstract

Neutrophilic inflammation with prolonged neutrophil survival is common to many inflammatory conditions, including chronic obstructive pulmonary disease (COPD). There are few specific therapies that reverse neutrophilic inflammation, but uncovering mechanisms regulating neutrophil survival is likely to identify novel therapeutic targets. Screening of 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbBs as common targets of compounds that accelerated inflammation resolution. The ErbB inhibitors gefitinib, CP-724714, erbstatin and tyrphostin AG825 significantly accelerated apoptosis of human neutrophils, including neutrophils from people with COPD. Neutrophil apoptosis was also increased in Tyrphostin AG825 treated-zebrafish in vivo. Tyrphostin AG825 decreased peritoneal inflammation in zymosan-treated mice, and increased lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. Tyrphostin AG825 and knockdown of egfra and erbb2 by CRISPR/Cas9 reduced inflammation in zebrafish. Our work shows that inhibitors of ErbB kinases have therapeutic potential in neutrophilic inflammatory disease.

Highlights

Neutrophilic inflammation is central to chronic inflammatory diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease (COPD), which impose an increasing social and economic burden on our aging population
A number of kinases were inhibited by the 16 compounds, with Abelson murine leukaemia viral homolog 1 (ABL1), Platelet-derived growth factor receptor (PDGFR) a, PDGFRb, p38a and ErbB4 being the top five most frequently targeted kinases overall
We show that neutrophil apoptosis was reduced by the cAMP analogue and site selective activator of PKA, N6-monobutyrylcAMP (N6-MB-cAMP), and that this was reversed by Erbstatin analog (Figure 3A) and Tyrphostin AG825 (Figure 3B)

Summary

Introduction

Neutrophilic inflammation is central to chronic inflammatory diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease (COPD), which impose an increasing social and economic burden on our aging population. Immunology and Inflammation eLife digest Chronic obstructive pulmonary disease (or COPD) is a serious condition that causes the lungs to become inflamed for long periods of time, leading to permanent damage of the airways. Immune cells known as neutrophils promote inflammation after an injury, or during an infection, to aid the healing process. If they are active for too long, they may cause tissue damage and drive inflammatory diseases including COPD. To limit damage to the body, neutrophils usually have a very short lifespan and die by a regulated process known as apoptosis. Finding ways to stimulate apoptosis in neutrophils may be key to developing better treatments for inflammatory diseases

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