Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
Biochim Biophys Acta Mol Basis Dis. 2022 Dec 1;1868(12):166490. doi: 10.1016/j.bbadis.2022.166490. Epub 2022 Jul 14.
Acute pancreatitis (AP) was initiated within pancreatic parenchymal cells and sustained by uncontrolled inflammatory responses. AXL and MERTK receptor tyrosine kinases play a crucial role in negatively regulating the innate immunity. Therefore, this study aimed to investigate the role and underlying mechanism of AXL and MERTK in AP.
Experimental AP was induced by ten hourly intraperitoneal administration of caerulein in global, hematopoietic- and pancreas-specific Axl and Mertk deficient mice. Pancreatitis severity was assessed biochemically and histologically. Pancreatic transcriptomics and pancreatic infiltrating immune cells were profiled. Some mice were given R428, an antagonist of AXL and MERTK. AXL and MERTK in peripheral leukocytes were measured by flow cytometry.
The levels of AXL and MERTK in pancreatic tissue and pancreatic CD45 cells were dynamically altered at 6 h and 12 h after the 1st injection of caerulein. Global and hematopoietic-specific, but not pancreas-specific deletion of Axl and Mertk protected against pancreatic necrosis and trypsinogen activation. Pancreatic transcriptomic analysis revealed that differentially expressed gene signatures were mainly related to metabolic and inflammatory pathways. Furthermore, deletion or inhibition of Axl and Mertk selectively inhibited pancreatic neutrophil infiltration, which was primarily related to CXCL2 secreted by pro-inflammatory macrophages. Increased levels of MERTK in peripheral leukocytes were correlated with more severe form of AP.
Our findings reveal that specific AXL/MERTK antagonist may be a novel and potential early treatment for AP and the levels of MERTK in peripheral leukocytes may be a promising biomarker for predicting pancreatic severity in patients with AP.
National Natural Science Foundation of China, Shanghai Natural Science Foundation, a Shanghai Young Talent Award and a Shanghai Young Orient Scholar Award.
Evidence before this study Acute pancreatitis (AP) is a common inflammatory disorder of the exocrine pancreas, the severity of which was determined by the extent of pancreatic necrosis, with no targeted therapy. AP was initiated by signals within pancreatic parenchymal cells and sustained by uncontrolled innate immune responses. One of the three crucial regulatory roles for AXL and MERTK is to negatively regulate innate immune responses. Added value of this study Global and hematopoietic-, but not pancreas-specific Axl and Mertk deficiency protected against pancreatitis, primarily pancreatic necrosis. Deletion of Axl and Mertk selectively inhibited pancreatic neutrophil infiltration that was related to CXCL2 secreted by pro-inflammatory macrophages. AXL and MERTK antagonist similarly reduced pancreatitis severity via limiting CXCL2-mediated pancreatic neutrophil infiltration. Higher levels of MERTK, but not AXL in peripheral leukocytes were correlated with more severe form of acute pancreatitis. Implications of all the available evidence A specific AXL/MERTK antagonist may be a novel and potential early treatment for AP. The level of MERTK on peripheral leukocytes may be a promising biomarker for predicting disease severity in patients with AP.
急性胰腺炎（AP）由胰腺实质细胞内的起始信号引发，并由失控的炎症反应持续。AXL 和 MERTK 受体酪氨酸激酶在负向调控固有免疫中起着至关重要的作用。因此，本研究旨在探讨 AXL 和 MERTK 在 AP 中的作用和潜在机制。
通过在全身性、造血细胞特异性和胰腺特异性 Axl 和 Mertk 缺陷小鼠中，每 10 小时腹腔内给予 caerulein，诱导实验性 AP。通过生化和组织学评估胰腺炎严重程度。对胰腺转录组和胰腺浸润免疫细胞进行分析。部分小鼠给予 AXL 和 MERTK 的拮抗剂 R428。通过流式细胞术测量外周血白细胞中的 AXL 和 MERTK。
在 caerulein 第 1 次注射后 6 小时和 12 小时，胰腺组织和胰腺 CD45 细胞中的 AXL 和 MERTK 水平呈动态变化。全身性和造血细胞特异性，而不是胰腺特异性的 Axl 和 Mertk 缺失可预防胰腺坏死和胰酶原激活。胰腺转录组分析显示，差异表达基因谱主要与代谢和炎症途径相关。此外，AXL 和 MERTK 的缺失或抑制选择性抑制了胰腺中性粒细胞浸润，这主要与促炎巨噬细胞分泌的 CXCL2 有关。外周血白细胞中 MERTK 水平的升高与 AP 更严重的形式相关。
我们的研究结果表明，特定的 AXL/MERTK 拮抗剂可能是 AP 的一种新的潜在早期治疗方法，外周血白细胞中 MERTK 的水平可能是预测 AP 患者胰腺严重程度的有前途的生物标志物。
急性胰腺炎（AP）是一种常见的胰腺外分泌炎症性疾病，其严重程度取决于胰腺坏死的程度，目前尚无靶向治疗方法。AP 由胰腺实质细胞内的信号引发，并由失控的固有免疫反应持续。AXL 和 MERTK 的三个关键调节作用之一是负向调节固有免疫反应。
全身性和造血细胞特异性，而不是胰腺特异性的 Axl 和 Mertk 缺失可预防胰腺炎，主要是胰腺坏死。AXL 和 MERTK 的缺失选择性抑制了与促炎巨噬细胞分泌的 CXCL2 有关的胰腺中性粒细胞浸润。AXL 和 MERTK 拮抗剂通过限制 CXCL2 介导的胰腺中性粒细胞浸润，同样减轻了胰腺炎的严重程度。外周血白细胞中 MERTK 的水平升高与更严重的急性胰腺炎形式相关，但 AXL 无此相关性。
特定的 AXL/MERTK 拮抗剂可能是 AP 的一种新的潜在早期治疗方法。外周血白细胞中 MERTK 的水平可能是预测 AP 患者疾病严重程度的有前途的生物标志物。
