Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

Author:

Rahman Atiqur12,Henry Katherine M13ORCID,Herman Kimberly D13,Thompson Alfred AR1ORCID,Isles Hannah M13,Tulotta Claudia13,Sammut David1,Rougeot Julien JY4,Khoshaein Nika1,Reese Abigail E1,Higgins Kathryn1,Tabor Caroline3,Sabroe Ian1,Zuercher William J5,Savage Caroline O6,Meijer Annemarie H4,Whyte Moira KB7,Dockrell David H17,Renshaw Stephen A13ORCID,Prince Lynne R1ORCID

Affiliation:

1. Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom

2. Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Dhaka, Dhaka, Bangladesh

3. The Bateson Centre, University of Sheffield, Sheffield, United Kingdom

4. Institute of Biology, Leiden University, Leiden, Netherlands

5. SGC-UNC, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, United States

6. Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline Research and Development Ltd, Stevenage, United Kingdom

7. MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

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.

Funder

Commonwealth Scholarship Commission

Medical Research Council

European Commission

SGC

British Heart Foundation

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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