The EGFR/ErbB inhibitor neratinib modifies the neutrophil phosphoproteome and promotes apoptosis and clearance by airway macrophages.

Autor:	Herman KD; Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, United Kingdom.; Department of Infection, Immunity and Cardiovascular Disease and The Bateson Centre, The Medical School, University of Sheffield, Sheffield, United Kingdom., Wright CG; Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, United Kingdom., Marriott HM; Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, United Kingdom., McCaughran SC; Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, United Kingdom., Bowden KA; Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, United Kingdom., Collins MO; Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom., Renshaw SA; Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, United Kingdom.; Department of Infection, Immunity and Cardiovascular Disease and The Bateson Centre, The Medical School, University of Sheffield, Sheffield, United Kingdom., Prince LR; Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, United Kingdom.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 Jul 28; Vol. 13, pp. 956991. Date of Electronic Publication: 2022 Jul 28 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.956991
Abstrakt:	Dysregulated neutrophilic inflammation can be highly destructive in chronic inflammatory diseases due to prolonged neutrophil lifespan and continual release of histotoxic mediators in inflamed tissues. Therapeutic induction of neutrophil apoptosis, an immunologically silent form of cell death, may be beneficial in these diseases, provided that the apoptotic neutrophils are efficiently cleared from the tissue. Previous research in our group identified ErbB inhibitors as able to induce neutrophil apoptosis and reduce neutrophilic inflammation both in vitro and in vivo . Here, we extend that work using a clinical ErbB inhibitor, neratinib, which has the potential to be repurposed in inflammatory diseases. We show that neratinib reduces neutrophilic migration o an inflammatory site in zebrafish larvae. Neratinib upregulates efferocytosis and reduces the number of persisting neutrophil corpses in mouse models of acute, but not chronic, lung injury, suggesting that the drug may have therapeutic benefits in acute inflammatory settings. Phosphoproteomic analysis of human neutrophils shows that neratinib modifies the phosphorylation of proteins regulating apoptosis, migration, and efferocytosis. This work identifies a potential mechanism for neratinib in treating acute lung inflammation by upregulating the clearance of dead neutrophils and, through examination of the neutrophil phosphoproteome, provides important insights into the mechanisms by which this may be occurring. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Herman, Wright, Marriott, McCaughran, Bowden, Collins, Renshaw and Prince.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu