AXL and MERTK in macrophages restore pancreatic exocrine function after severe acute pancreatitis by modulating acinar-to-ductal metaplasia formation.

Severe acute pancreatitis (SAP) often leads to incomplete tissue repair and prolonged exocrine dysfunction. Acinar-to-ductal metaplasia (ADM) is a critical regenerative process postinjury, but persistent ADM impedes functional recovery. Axl and Mertk belong to the TAM family of receptor tyrosine kinases, which are expressed primarily in macrophages to mediate efferocytosis and promote pro-resolving macrophage polarization, and have been implicated in tissue repair. However, their roles in resolving ADM and restoring exocrine function remain unclear. We utilized cerulein-induced SAP models in mice with either global or cell-specific deletion of Axl and Mertk. Pancreatic repair was assessed by histology, transcriptomics, and functional assays. Coculture of primary acinar cells with bone marrow-derived macrophages. The expression of AXL and MERTK in the pancreas was upregulated on Day 4 during pancreatic repair after SAP. Global deletion of Axl and Mertk similarly delayed tissue repair, resulting in persistent ADM, impaired acinar redifferentiation, and defective restoration of exocrine function. Transcriptomics revealed aberrant activation of developmental signaling pathways, including Hedgehog, Wnt, and Notch, and sustained suppression of acinar digestive enzyme genes. In vitro coculture experiments showed that M2 macrophages lacking Axl and Mertk promoted persistent ADM, in contrast to M1 macrophages. AXL and MERTK in macrophages are crucial regulators of pancreatic regeneration after SAP, facilitating ADM resolution and exocrine recovery through interactions between acinar cells and M2 macrophages. These findings highlight that macrophage AXL and MERTK could act as a potential therapeutic target for enhancing long-term restoration of pancreatic function following SAP.NEW & NOTEWORTHY Deleting Axl and Mertk in myeloid cells disrupts the healing process, resulting in persistent ductal structures and failure to recover exocrine function. This repair failure is linked to the abnormal persistence of developmental signaling pathways and is mediated by interactions between acinar cells and macrophages, emphasizing the importance of AXL and MERTK in macrophages in pancreatic functional recovery.