Synthetic cleavage-resistant TREM2 boosts macrophage efferocytosis to treat inflammatory diseases

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Triggering receptor expressed on myeloid cells 2 (TREM2) is crucial for macrophage efferocytosis and tissue homeostasis.
• Inflammation-induced ADAM17 cleaves TREM2, impairing efferocytosis and worsening inflammatory conditions.

Purpose of the Study:

• To engineer a synthetic, cleavage-resistant TREM2 (CRT) to enhance TREM2-dependent efferocytosis.
• To evaluate CRT's efficacy in mitigating inflammation linked to accumulated apoptotic cells.

Main Methods:

• CRT was designed by linking the TREM2 ligand-binding domain to the DAP12 adaptor via a modified stalk and transmembrane segment.
• CRT mRNA was delivered into macrophages using lipid nanoparticles to create CRT-engineered macrophages (CRT-Ms) in situ.
• CRT-Ms' efficacy was tested in mouse models of metabolic-dysfunction-associated steatohepatitis and atherosclerosis.

Main Results:

• CRT amplifies TREM2 signaling, remaining effective even with ADAM17 activity.
• CRT-Ms demonstrated efficient reduction of apoptotic cell burden in vivo.
• Treatment with CRT-Ms significantly alleviated inflammation in disease models.

Conclusions:

• CRT represents a strategy to bolster TREM2-mediated efferocytosis, counteracting cleavage by ADAM17.
• CRT-engineered macrophages show therapeutic potential for diseases characterized by excessive apoptotic cell accumulation and inflammation.