Immunological Aspects of AXL/GAS‐6 in the Context of Human Liver Regeneration

作者：Gregor Ortmayr, Laura Brunnthaler, David Pereyra, Heidemarie Huber, Jonas Santol, Benedikt Rumpf, S. Najarnia, Rory L. Smoot, Daphni Ammon, Thomas Sorz, Fabian Fritsch, Michael Schodl, Astrid Voill‐Glaninger, Barbara Weitmayr, Manuela Födinger, M. Klimpfinger, Thomas Gruenberger, Alice Assinger, Wolfgang Mikulits, Patrick Starlinger · 发表于：Hepatology Communications · 年份：2021 · DOI：10.1002/hep4.1832 · 被引用次数：11 · 研究领域：Phagocytosis and Immune Regulation、Liver physiology and pathology、Pancreatic and Hepatic Oncology Research

AXL and its corresponding ligand growth arrest-specific 6 (GAS-6) are critically involved in hepatic immunomodulation and regenerative processes. Pleiotropic inhibitory effects on innate inflammatory responses might essentially involve the shift of macrophage phenotype from a pro-inflammatory M1 to an anti-inflammatory M2. We aimed to assess the relevance of the AXL/GAS-6-pathway in human liver regeneration and, consequently, its association with clinical outcome after hepatic resection. Soluble AXL (sAXL) and GAS-6 levels were analyzed at preoperative and postoperative stages in 154 patients undergoing partial hepatectomy and correlated with clinical outcome. Perioperative dynamics of interleukin (IL)-6, soluble tyrosine-protein kinase MER (sMerTK), soluble CD163 (sCD163), and cytokeratin (CK) 18 were assessed to reflect pathophysiological processes. Preoperatively elevated sAXL and GAS-6 levels predicted postoperative liver dysfunction (area under the curve = 0.721 and 0.722; P < 0.005) and worse clinical outcome. These patients failed to respond with an immediate increase of sAXL and GAS-6 upon induction of liver regeneration. Abolished AXL pathway response resulted in a restricted increase of sCD163, suggesting a disrupted phenotypical switch to regeneratory M2 macrophages. No association with sMerTK was observed. Concomitantly, a distinct association of IL-6 levels with an absent increase of AXL/GAS-6 signaling indicated pronounced postoperative inflammation. This was fu...