Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation
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Abstract
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.
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EGFR inhibitors promote resolution of neutrophilic inflammation.
“EGFR inhibitors have also been shown to promote the resolution of neutrophilic inflammation”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Rahman et al., 2019
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Immunomodulation by targeted anticancer agents
Petroni, G., Buqué, A., Zitvogel, L., Kroemer, G., & Galluzzi, L. (2021) · Cancer Cell · doi:10.1016/j.ccell.2020.11.009 · Cited by 212 · see citing works
- Authors
- Rahman, A., Henry, K. M., Herman, K. D., Thompson, A. A., Isles, H. M., Tulotta, C., Sammut, D., Rougeot, J. J., Khoshaein, N., Reese, A. E., Higgins, K., Tabor, C., Sabroe, I., Zuercher, W. J., Savage, C. O., Meijer, A. H., Whyte, M. K., Dockrell, D. H., Renshaw, S. A., & Prince, L. R.
- Affiliations
- University of Dhaka (BD)
- University of Sheffield (GB)
- Leiden University (NL)
- University of North Carolina at Chapel Hill (US)
- GlaxoSmithKline (United Kingdom) (GB)
- Centre for Inflammation Research (GB)
- Corresponding author
- Renshaw, Stephen A
- Prince, Lynne R
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2019-10-15
- Volume
- 8
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6839918
- OpenAlex
- W2980719126
- Cited by
- 38
- References
- 81
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 8 · 2020: 7
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Leiden Repository (Leiden University) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Funders
- Commonwealth Scholarship Commission
- Medical Research Council (MR/M004864/1, G0700091)
- European Commission (PITG-GA-2011-289209)
- SGC
- British Heart Foundation (Intermediate Clinician Fellowship FS/18/13/33281)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- neutrophilic inflammation, neutrophil apoptosis, inflammation resolution, chronic obstructive pulmonary disease, tyrosine kinase inhibitors, gefitinib, erbstatin, EGFR, ERBB2, efferocytosis, acute lung injury
- MeSH terms
- Animals, Cells, Cultured, Disease Models, Animal, Humans, Inflammation, Lung, Neutrophils, Pseudomonas Infections, Zebrafish, Treatment Outcome, Pneumonia, Bacterial, Tyrphostins, Protein Kinase Inhibitors, Mice, Benzothiazoles, Animal Fins, ErbB Receptors
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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