Ligand-dependent kinase activity of MERTK drives efferocytosis in human iPSC-derived macrophages

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Efferocytosis, the removal of apoptotic cells by phagocytes, is critical for tissue homeostasis and preventing inflammation.
• TAM receptor tyrosine kinases (RTKs), including MERTK and AXL, are known to be involved in efferocytosis, particularly in murine models.
• The precise function of human TAM RTKs in efferocytosis remains less understood.

Purpose of the Study:

• To investigate the role of TAM RTKs, specifically MERTK and AXL, in human efferocytosis.
• To determine the necessity of MERTK kinase activity for efferocytosis in both murine and human systems.
• To explore the potential of targeting TAM RTKs for therapeutic interventions in efferocytosis-related disorders.

Main Methods:

• Differentiated human macrophages from induced pluripotent stem cells (iPSC) for in vitro studies.
• Utilized a novel mouse model with kinase-dead MERTK to assess in vivo efferocytosis.
• Employed blocking antibodies and small molecule inhibitors to target TAM RTKs in human macrophages.

Main Results:

• Human iPSC-derived macrophages express both AXL and MERTK and effectively engulf apoptotic cells.
• Growth-arrest specific 6 (GAS6), a natural ligand for TAM RTKs, significantly enhanced efferocytosis.
• MERTK kinase activity was demonstrated to be essential for efferocytosis in murine peritoneal macrophages in vivo.
• Inhibition of MERTK in human macrophages recapitulated the findings from the murine model, confirming its conserved role.

Conclusions:

• MERTK kinase activity is crucial for effective efferocytosis in both mice and humans.
• This study establishes a conserved functional role for MERTK in homeostatic efferocytosis across species.
• The findings underscore the importance of MERTK in maintaining tissue health and suggest its potential as a therapeutic target.