228.3: Defective efferocytosis by aged macrophages promotes STING signaling mediated inflammatory liver injury.

Background and Aims: Timely efferocytosis of apoptotic cells is a key mechanism for avoiding excessive inflammation and tissue injury. MerTK (c-mer proto-oncogene tyrosine kinase), a member of the TAM (Tyro3, Axl, and MerTK) family, plays an essential role in the regulation of efferocytosis. We previously found that aging promoted macrophage STING (stimulator of interferon genes) activation to aggravate inflammatory liver injury. Here, we investigated the alteration of efferocytosis by aged macrophages and its role in regulating macrophage STING signaling and ischemic liver injury. Method: Young (8 weeks) and aged (100 weeks) STING myeloid-specific Cre mice and wild-type mice were subjected to a model of liver ischemia and reperfusion. Efferocytosis by macrophages was analyzed in vivo and in vitro macrophages co-cultured with apoptotic Jurkat cells. The MerTK CRISPR activation plasmid, ADAM17 (a disintegrin and metalloproteinase 17) siRNA and N-acetylcysteine were used to conduct rescue experiments. Results: Aged macrophages exhibited impaired efferocytosis with decreased MerTK activation, which was reversed by treatment with the MerTK CRISPR activation plasmid. Increased MerTK cleavage by ADAM17 due to enhanced ROS levels contributed to defective MerTK-mediated efferocytosis by aged macrophages. MerTK activation by suppressing ADAM17 or ROS improves aged macrophage efferocytosis, leading to reduced liver inflammation and IR injury. Moreover, increased apoptotic hepatocytes, DNA accumulation, and macrophage STING activation were observed in aged livers post-IR. Improvement in efferocytosis by aged macrophages via MerTK activation suppressed STING activation and inflammatory liver injury. Conclusion: 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 aging. The National Natural Science Foundation of China (82071798).