2. Academic Validation
  3. Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

  • Elife. 2019 Oct 15;8:e50990. doi: 10.7554/eLife.50990.
Atiqur Rahman 1 2,  Katherine M Henry 1 3,  Kimberly D Herman 1 3,  Alfred Ar Thompson 1,  Hannah M Isles 1 3,  Claudia Tulotta 1 3,  David Sammut 1,  Julien Jy Rougeot 4,  Nika Khoshaein 1,  Abigail E Reese 1,  Kathryn Higgins 1,  Caroline Tabor 3,  Ian Sabroe 1,  William J Zuercher 5,  Caroline O Savage 6,  Annemarie H Meijer 4,  Moira Kb Whyte 7,  David H Dockrell 1 7,  Stephen A Renshaw  # 1 3,  Lynne R Prince  # 1
Affiliations

Affiliations

  • 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.
  • # Contributed equally.
PMID: 31613219 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.

Keywords

apoptosis; human; immunology; inflammation; mouse; neutrophil; protein kinase; zebrafish.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z