Li Bin, Zhang Xiuli, Liu Song, Guo Xiaoyu, Lu Wanyi, Peng Kaixin, Liu Rujuan, Chen Zhigao, Li Liang, Hu Guoyong, Husain Sohail, Wang Xingpeng, Wen Li
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Center for Biomarker Discovery and Validation, National Infrastructures for Translational Medicine (PUMCH), Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.
Cell Commun Signal. 2025 Sep 2;23(1):388. doi: 10.1186/s12964-025-02412-8.
Severe acute pancreatitis (SAP) is a potentially life-threatening inflammatory disorder of the exocrine pancreas, characterized by massive cell death, which drives the progression and resolution of the disease. However, little is known about the key regulators in the tissue microenvironment that mediate tissue damage and repair. In this study, we discovered that AXL and MERTK in macrophages are responsible for tissue repair and pancreatic inflammation following SAP. Targeted deletion of Axl and Mertk in myeloid cells resulted in impaired phenotypic switch towards pro-resolving macrophage. This impairment is partly due to an accumulation of Cxcr2 neutrophils and its interaction with Mrc1 macrophages likely via CCL4-CCR5 axis. Pancreatic tissue repair was effectively restored by CCR5 inhibition. Collectively, we identify a CCR5-dependent pathway orchestrated by AXL and MERTK in macrophages, which offers a pharmacological target, to promote tissue repair in SAP.
重症急性胰腺炎（SAP）是一种可能危及生命的胰腺外分泌腺炎症性疾病，其特征是大量细胞死亡，这推动了疾病的进展和转归。然而，对于介导组织损伤和修复的组织微环境中的关键调节因子知之甚少。在本研究中，我们发现巨噬细胞中的AXL和MERTK负责SAP后的组织修复和胰腺炎症。髓系细胞中Axl和Mertk的靶向缺失导致向促消退巨噬细胞的表型转换受损。这种损伤部分归因于Cxcr2中性粒细胞的积累及其与Mrc1巨噬细胞可能通过CCL4-CCR5轴的相互作用。通过抑制CCR5可有效恢复胰腺组织修复。总体而言，我们确定了巨噬细胞中由AXL和MERTK协调的CCR5依赖性途径，这提供了一个药理学靶点，以促进SAP中的组织修复。
