Brozat Jonathan F, Brandt Elisa F, Stark Myriam, Fischer Petra, Wirtz Theresa H, Flaßhove Alexander, Rodenhausen Aaron N, Vajen Tanja, Heinzmann Alexandra C A, Schmitz Sophia M-T, Abu Jhaisha Samira, Röth Anjali A, Koenen Rory R, Sahin Hacer, Trautwein Christian, Berres Marie-Luise
Department of Internal Medicine III, RWTH Aachen University Hospital, RWTH Aachen, Aachen, Germany.
Cardiovascular Research Laboratory, Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Liver Int. 2022 May;42(5):1185-1203. doi: 10.1111/liv.15187. Epub 2022 Mar 11.
Leukocyte infiltration is a hallmark of hepatic inflammation. The Junctional Adhesion Molecule A (JAM-A) is a crucial regulator of leukocyte extravasation and is upregulated in human viral fibrosis. Reduced shear stress within hepatic sinusoids and the specific phenotype of liver sinusoidal endothelial cells (LSEC) cumulate in differing adhesion characteristics during liver fibrosis. The aim of this study was to define the functional role of cell-specific adhesion molecule JAM-A during hepatic fibrogenesis.
Complete, conditional (intestinal epithelial; endothelial) and bone marrow chimeric Jam-a knockout animals and corresponding C57Bl/6 wild-type animals were treated with carbon tetrachloride (CCl , 6 weeks). For functional analyses of JAM-A, comprehensive in vivo studies, co-culture models and flow-based adhesion assays were performed.
Complete and bone marrow-derived Jam-a animals showed aggravated fibrosis with increased non-sinusoidal, perivascular accumulation of CD11b F4/80 monocyte-derived macrophages in contrast to wild-type mice. Despite being associated with disturbed epithelial barrier function, an intestinal epithelial Jam-a knockout did not affect fibrogenesis. In endothelial-specific Jam-a animals, liver fibrosis was aggravated alongside sinusoid capillarization and hepatic stellate cell (HSC) activation. HSC activation is induced via Jam-a LSEC-derived secretion of soluble factors. Sinusoid CD31 expression and hedgehog gene signalling were increased, but leukocyte infiltration and adhesion to LSECs remained unaffected.
Our models decipher cell-specific JAM-A to exert crucial functions during hepatic fibrogenesis. JAM-A on bone marrow-derived cells regulates non-sinusoidal vascular immune cell recruitment, while endothelial JAM-A controls liver sinusoid capillarization and HSC quiescence.
白细胞浸润是肝脏炎症的一个标志。连接黏附分子A（JAM-A）是白细胞外渗的关键调节因子，在人类病毒性肝纤维化中上调。肝血窦内剪切应力降低以及肝窦内皮细胞（LSEC）的特定表型在肝纤维化过程中累积形成不同的黏附特性。本研究的目的是确定细胞特异性黏附分子JAM-A在肝纤维化形成过程中的功能作用。
用四氯化碳（CCl ，6周）处理完全性、条件性（肠上皮；内皮）和骨髓嵌合的Jam-a基因敲除动物以及相应的C57Bl/6野生型动物。为了对JAM-A进行功能分析，进行了全面的体内研究、共培养模型和基于流式细胞术的黏附试验。
与野生型小鼠相比，完全性和骨髓来源的Jam-a基因敲除动物表现出更严重的纤维化，CD11b F4/80单核细胞来源的巨噬细胞在非血窦、血管周围的积聚增加。尽管与上皮屏障功能紊乱有关，但肠上皮Jam-a基因敲除并不影响纤维化形成。在内皮细胞特异性Jam-a基因敲除动物中，肝纤维化加重，同时伴有血窦毛细血管化和肝星状细胞（HSC）激活。HSC激活是通过Jam-a基因LSEC分泌的可溶性因子诱导的。血窦CD31表达和刺猬基因信号增加，但白细胞浸润和对LSECs的黏附未受影响。
我们的模型揭示了细胞特异性JAM-A在肝纤维化形成过程中发挥关键作用。骨髓来源细胞上的JAM-A调节非血窦血管免疫细胞募集，而内皮细胞JAM-A控制肝血窦毛细血管化和HSC静止。
