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Background <p>Chronic inflammatory disease is responsible for huge and increasing global mortality and morbidity. Unregulated inflammatory cells, including neutrophils and macrophages, are major drivers of chronic inflammatory disease. Efferocytosis plays a critical role in inflammation resolution by removing effete inflammatory cells from tissues. Despite defective efferocytosis being critical in inflammatory disease progression there are no therapies to correct these defects in clinical use. Here, using experimental models of atherosclerosis and lung injury, we identify the ErbB family tyrosine kinase inhibitor (TKI), neratinib, as a putative efferocytosis-targeting therapy.</p> Results <p>In an experimental model of atherosclerosis and lung injury, two doses of neratinib significantly increased efferocytosis in the lungs of mice concomitant with a reduction in the proportion of lung neutrophils. Neratinib significantly increased human neutrophil apoptosis and efferocytosis of apoptotic neutrophils by monocyte-derived macrophages (MDMs). In addition to increased efferocytosis, neratinib treated macrophages demonstrated both increased phagocytosis and macropinocytosis. Neratinib increased MDM surface expression of the efferocytosis receptor MerTK independent of protein synthesis and transcription which correlated with elevated efferocytosis in MDMs and inhibitors of MerTK blocked neratinib-induced efferocytosis.</p> Conclusions <p>Thus, we describe a novel role for neratinib in driving efferocytosis in multimorbidity and suggest that ErbB TKIs may have therapeutic potential in inflammatory disease by restoring macrophage function and promoting inflammation resolution.</p>

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The ErbB-tyrosine kinase inhibitor, neratinib, has anti-inflammatory effects in multimorbidity by increasing macrophage efferocytosis via the upregulation of MerTK

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月19日

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  • Kieran A. Bowden,
  • Carl Wright,
  • Susan Clark,
  • Tomas Fernandez Correa,
  • Simon A. Johnston,
  • Helen M. Marriott,
  • Sheila E. Francis,
  • Lynne R. Prince

摘要

Background

Chronic inflammatory disease is responsible for huge and increasing global mortality and morbidity. Unregulated inflammatory cells, including neutrophils and macrophages, are major drivers of chronic inflammatory disease. Efferocytosis plays a critical role in inflammation resolution by removing effete inflammatory cells from tissues. Despite defective efferocytosis being critical in inflammatory disease progression there are no therapies to correct these defects in clinical use. Here, using experimental models of atherosclerosis and lung injury, we identify the ErbB family tyrosine kinase inhibitor (TKI), neratinib, as a putative efferocytosis-targeting therapy.

Results

In an experimental model of atherosclerosis and lung injury, two doses of neratinib significantly increased efferocytosis in the lungs of mice concomitant with a reduction in the proportion of lung neutrophils. Neratinib significantly increased human neutrophil apoptosis and efferocytosis of apoptotic neutrophils by monocyte-derived macrophages (MDMs). In addition to increased efferocytosis, neratinib treated macrophages demonstrated both increased phagocytosis and macropinocytosis. Neratinib increased MDM surface expression of the efferocytosis receptor MerTK independent of protein synthesis and transcription which correlated with elevated efferocytosis in MDMs and inhibitors of MerTK blocked neratinib-induced efferocytosis.

Conclusions

Thus, we describe a novel role for neratinib in driving efferocytosis in multimorbidity and suggest that ErbB TKIs may have therapeutic potential in inflammatory disease by restoring macrophage function and promoting inflammation resolution.