Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines

✍ Scribed by Arnhild Schrage; Katja Wechsung; Katrin Neumann; Michael Schumann; Jörg-Dieter Schulzke; Britta Engelhardt; Martin Zeitz; Alf Hamann; Katja Klugewitz

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 944 KB
• Volume: 48
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.22443

✦ Synopsis

Transmigration through the liver endothelium is a prerequisite for the homeostatic balance of intrahepatic T cells and a key regulator of inflammatory processes within the liver. Extravasation into the liver parenchyma is regulated by the distinct expression patterns of adhesion molecules and chemokines and their receptors on the lymphocyte and endothelial cell surface. In the present study, we investigated whether liver sinusoidal endothelial cells (LSEC) inhibit or support the chemokine-driven transmigration and differentially influence the transmigration of pro-inflammatory or anti-inflammatory CD4 ؉ T cells, indicating a mechanism of hepatic immunoregulation. Finally, the results shed light on the molecular mechanisms by which LSEC modulate chemokine-dependent transmigration. LSEC significantly enhanced the chemotactic effect of CXC-motif chemokine ligand 12 (CXCL12) and CXCL9, but not of CXCL16 or CCL20, on naive and memory CD4 ؉ T cells of a T helper 1, T helper 2, or interleukin-10producing phenotype. In contrast, brain and lymphatic endothelioma cells and ex vivo isolated lung endothelia inhibited chemokine-driven transmigration. As for the molecular mechanisms, chemokine-induced activation of LSEC was excluded by blockage of G i -protein-coupled signaling and the use of knockout mice. After preincubation of CXCL12 to the basal side, LSEC took up CXCL12 and enhanced transmigration as efficiently as in the presence of the soluble chemokine. Blockage of transcytosis in LSEC significantly inhibited this effect, and this suggested that chemokines taken up from the basolateral side and presented on the luminal side of endothelial cells trigger T cell transmigration. Conclusion: Our findings demonstrate a unique capacity of LSEC to present chemokines to circulating lymphocytes and highlight the importance of endothelial cells for the in vivo effects of chemokines. Chemokine presentation by LSEC could provide a future therapeutic target for inhibiting lymphocyte immigration and suppressing hepatic inflammation. (HEPATOLOGY 2008;48:1262-1272.)

H omeostatic extravasation into the liver parenchyma and transmigration of T cells into sites of inflammation under pathological conditions such as hepatitis and cholangitis are mediated by multiple steps involving activation and firm adhesion followed by egress. The process is closely regulated by the distinct expression patterns of adhesion molecules and chemokines and their receptors on the cell surface. 1,2 Within the liver, lymphocyte adhesion, a prerequisite for transmigration, occurs mainly within the sinusoidal circulation. Thus, T cell immigration into the liver is presumed to happen predominantly via the sinusoids. 3 Liver sinusoidal endothelial cells (LSEC) lining the sinusoids form a morphologically and functionally distinct endothelium that lacks a basement membrane, fails to form tight junctions, and displays fenestrae grouped to sieve plates. 4 In contrast to other tissues, selectins are not necessary for the initial adhesion of leukocytes to the liver microvasculature. The