| Description |
Liver ischemia-reperfusion injury (LIRI) is an inevitable detrimental event following liver transplantation, significantly impacting clinical outcomes. Mas, a G protein-coupled receptor, has been demonstrated to have a protective role in various diseases. However, Mas specific roles in myeloid cell innate immunity and the maintenance of hepatic tissue homeostasis remain unclear. Here, we show that mice with systemic, kupffer cell-specific or myeloid cell-specific Mas1 deficiency were all vulnerable to LIRI. Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and intravital imaging multidimensionally revealed that myeloid deficiency of Mas1 results in impaired macrophage efferocytosis by downregulating MerTK, leading to the accumulation of aged neutrophils and exacerbating inflammation and pathology. Mechanistic studies indicated that Mas receptor regulates the KLF4/MerTK axis in macrophage through the PKA/CREB signaling pathway. Transcription factor KLF4 directly bound to the promotor region of MerTK, and transcriptionally promoted its expression in macrophage, leading to attenuation of liver inflammatory response. Macrophage-specific knockout of KLF4 and macrophage-specific knockout of MerTK also results in impaired macrophage efferocytosis with the accumulation of aged neutrophils. Macrophage-specific overexpression of KLF4 in vivo effectively reversed the exacerbated phenotype caused by myeloid Mas1 deficiency. Additionally, we also demonstrated that Mas+MerTK+ macrophages actively migrate towards aged neutrophils in ischemia-stressed human livers, thereby promptly clearing aged neutrophils. In summary, this study documents a regulatory function of the Mas/KLF4/MerTK axis via PKA/CREB signaling in macrophage effercytosis. It may serve as a therapeutic target and as a checkpoint regulator of homeostasis in response to LIRI. |
