Suppression of Cardiac Allograft Vasculopathy by a Macrophage Efferocytosis Receptor

Authors

Sahil Shah
Aparnaa Ananthakrishnan
Matthew DeBerge
Kristofor Glinton
Rebecca T L Jones
Mallory Filipp
Ivana Shen
Joey Lockhart
Connor W Lantz
Edward B Thorp

Language

English

Publication Date

8-26-2025

Journal

American Journal of Transplantation

DOI

10.1016/j.ajt.2025.08.026

PMID

40865877

PMCID

PMC12677151

PubMedCentral® Posted Date

12-5-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Cardiac allograft vasculopathy remains a major cause of late morbidity following heart transplantation. While accumulating evidence implicates innate macrophages in the inflammatory progression of CAV, the underlying mechanisms remain incompletely understood. In murine models of CAV, we identified proteolytic cleavage of MERTK, a key anti-inflammatory receptor on macrophages, as a contributing factor to CAV progression. In a model of CAV, MERTK deficiency accelerated allograft rejection and increased intimal leukocyte infiltration. In contrast, mice expressing a genetically cleavage-resistant form of MERTK (MertkCR/CR) exhibited prolonged graft survival, reduced intimal thickening, diminished immune cell infiltration, and decreased circulating effector T cells. Macrophages isolated from MertkCR/CR allografts had enhanced mitochondrial metabolism, which correlated with the production of anti-inflammatory cytokines including IL-10. Mechanistically, co-culture experiments demonstrated activated CD8+ T cells, and not CD4+ or naïve CD8+ T cells, induce MERTK cleavage on macrophages leading to reduced efferocytosis, increased glycolysis, and increased inflammatory cytokine expression. Together, our findings identify MERTK as a critical regulator of macrophages efferocytosis and metabolism in the context of cardiac transplantation. Our data suggest that MERTK activity protects against CAV progression and that activated T cells may promote allograft injury, in part, by driving MERTK proteolysis.

Keywords

Macrophage, Efferocytosis, Transplant, Vasculopathy

Published Open-Access

yes

Recommended Citation

Shah, Sahil; Ananthakrishnan, Aparnaa; DeBerge, Matthew; et al., "Suppression of Cardiac Allograft Vasculopathy by a Macrophage Efferocytosis Receptor" (2025). Faculty, Staff and Student Publications. 5525.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5525