Aged livers have shown aggravated liver
ischemia and reperfusion (IR) injury. Timely efferocytosis of apoptotic cells is a key mechanism for avoiding excessive
inflammation and tissue injury. Here, we investigated the alteration of efferocytosis by aged macrophages and its role in regulating macrophage
STING (stimulator of
interferon genes) signaling and liver IR injury. Aged and young mice were subjected to liver partial IR model. Liver injury and
inflammation were measured. Efferocytosis by aged macrophages and the underlying regulatory mechanism were analyzed as well. Aged macrophages exhibited impaired efferocytosis with decreased
MerTK (
c-mer proto-oncogene tyrosine kinase) activation, which was reversed by treatment of the
MerTK CRISPR activation plasmid. Increased
MerTK cleavage by ADAM17 (a
disintegrin and
metalloproteinase 17) due to enhanced ROS (
reactive oxygen species) levels contributed to defective efferocytosis by aged macrophages.
MerTK activation by suppressing ADAM17 or ROS improved aged macrophage efferocytosis, leading to reduced inflammatory liver injury. Moreover, increased apoptotic hepatocytes,
DNA accumulation, and macrophage
STING activation were observed in aged ischemic livers. Improvement in efferocytosis by aged macrophages via
MerTK activation suppressed
STING activation and inflammatory liver injury. Our study demonstrates that aging suppresses
MerTK- mediated macrophage efferocytosis to promote macrophage
STING activation and inflammatory liver IR injury, suggesting a new mechanism and potential
therapy to promote
inflammation resolution and efferocytosis in aged livers.