Suppression of cardiac allograft vasculopathy by a macrophage efferocytosis receptor

Area of Science:

• Immunology
• Transplantation Biology
• Macrophage Biology

Background:

• Cardiac allograft vasculopathy (CAV) is a primary cause of late morbidity after heart transplantation.
• Innate macrophages are implicated in CAV progression, but the precise mechanisms are not fully understood.
• The anti-inflammatory receptor MERTK on macrophages plays a role in regulating immune responses.

Purpose of the Study:

• To investigate the role of MERTK proteolytic cleavage in the progression of cardiac allograft vasculopathy (CAV).
• To determine the impact of MERTK function on allograft rejection and inflammatory responses.
• To elucidate the mechanisms by which T cells influence MERTK activity and macrophage function in transplantation.

Main Methods:

• Utilized murine models of CAV to study MERTK deficiency and a cleavage-resistant MERTK mutant (Mertk ^CR/CR).
• Assessed allograft rejection, intimal thickening, immune cell infiltration, and circulating effector T cells.
• Analyzed macrophage mitochondrial metabolism, cytokine production (e.g., IL-10), efferocytosis, and glycolysis in vitro and in vivo.

Main Results:

• MERTK deficiency accelerated allograft rejection and increased leukocyte infiltration in CAV models.
• Mertk ^CR/CR mice showed prolonged graft survival, reduced intimal thickening, and diminished immune cell infiltration.
• Macrophages from Mertk ^CR/CR allografts exhibited enhanced mitochondrial metabolism and produced more IL-10.
• Activated CD8+ T cells, but not CD4+ or naive CD8+ T cells, induced MERTK cleavage, reducing efferocytosis and increasing inflammation.

Conclusions:

• MERTK is a critical regulator of macrophage efferocytosis and metabolism in cardiac transplantation.
• MERTK activity protects against CAV progression.
• Activated T cells promote allograft injury by driving MERTK proteolysis, highlighting MERTK as a potential therapeutic target.