Immunological Aspects of AXL/GAS-6 in the Context of Human Liver Regeneration.
Immunological Aspects of AXL/GAS-6 in the Context of Human Liver Regeneration.
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在人肝脏再生的背景下，AXL/GAS-6的免疫学方面。
DOI：
10.1002/hep4.1832
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发表时间：
2022-03
影响因子：
5.1
通讯作者：
Starlinger P
中科院分区：
文献类型：
--
作者：
Ortmayr G;Brunnthaler L;Pereyra D;Huber H;Santol J;Rumpf B;Najarnia S;Smoot R;Ammon D;Sorz T;Fritsch F;Schodl M;Voill-Glaninger A;Weitmayr B;Födinger M;Klimpfinger M;Gruenberger T;Assinger A;Mikulits W;Starlinger P
AXL及其相应的配体生长抑制特异性6（GAS-6）在肝脏免疫调节和再生过程中发挥重要作用。对先天性炎症反应的多效性抑制作用可能主要涉及巨噬细胞表型从促炎M1转变为抗炎M2。我们的目的是评估AXL/GAS-6-通路在人类肝再生中的相关性，以及其与肝切除术后临床结局的相关性。在154例接受部分肝切除术的患者中，分析了术前和术后阶段的可溶性AXL（sAXL）和GAS-6水平，并与临床结局相关。评估围手术期白细胞介素（IL）-6、可溶性酪氨酸蛋白激酶MER（sMerTK）、可溶性CD 163（sCD 163）和细胞角蛋白（CK）18的动态变化，以反映病理生理过程。术前升高的sAXL和GAS-6水平预测术后肝功能障碍（曲线下面积= 0.721和0.722; P < 0.005）和更差的临床结局。这些患者在诱导肝再生后未能立即增加sAXL和GAS-6。废除AXL途径的反应，导致有限的增加sCD 163，这表明一个破坏的表型转换为再生M2巨噬细胞。未观察到与sMerTK相关。同时，IL-6水平与AXL/GAS-6信号不增加的明显相关性表明术后炎症明显。这进一步得到了肝内继发性坏死增加的支持，如CK 18 M65所反映的。sAXL和GAS-6不仅代表术后结果的有效且易于获得的术前生物标志物，而且AXL/GAS-6信号传导可能与人类肝再生至关重要。难治性AXL/GAS-6信号传导，由于在基础肝病的背景下慢性过度激活/刺激，似乎在诱导肝再生后消除了它们的立即释放，引起压倒性的免疫激活，可能是通过肝内免疫调节。
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 further supported by increased intrahepatic secondary necrosis as reflected by CK18M65. sAXL and GAS‐6 represent not only potent and easily accessible preoperative biomarkers for the postoperative outcome but also AXL/GAS‐6 signaling might be of critical relevance in human liver regeneration. Refractory AXL/GAS‐6 signaling, due to chronic overactivation/stimulation in the context of underlying liver disease, appears to abolish their immediate release following induction of liver regeneration, causing overwhelming immune activation, presumably via intrahepatic immune regulation.
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影响因子：
13.5
作者：
Llacuna, Laura;Barcena, Cristina;Bellido-Martin, Lola;Fernandez, Laura;Stefanovic, Milica;Mari, Montserrat;Garcia-Ruiz, Carmen;Fernandez-Checa, Jose C.;Garcia de Frutos, Pablo;Morales, Albert
通讯作者：
Morales, Albert
影响因子：
5.8
作者：
Dixon LJ;Barnes M;Tang H;Pritchard MT;Nagy LE
通讯作者：
Nagy LE
影响因子：
4.1
作者：
Ju, C;Reilly, TP;Pohl, LR
通讯作者：
Pohl, LR
影响因子：
13.5
作者：
Bourdi, M;Masubuchi, Y;Pohl, LR
通讯作者：
Pohl, LR
影响因子：
4.6
作者：
Marchetti, Valentina;Yanes, Oscar;Aguilar, Edith;Wang, Matthew;Friedlander, David;Moreno, Stacey;Storm, Kathleen;Zhan, Min;Naccache, Samia;Nemerow, Glen;Siuzdak, Gary;Friedlander, Martin
通讯作者：
Friedlander, Martin