Chemokine presentation by liver sinusoidal endothelial cells as therapeutic target in murine T cell-mediated hepatitis

Background & aims: Leukocyte adhesion and transmigration is one of the central paradigms of inflammation. Within the liver sinusoids, chemokines initiate the first crucial step of lymphocyte migration into the parenchyma. Particularly liver sinusoidal endothelial cells (LSEC) present chemokines increasing their biological activity. We here investigated mechanisms of chemokine transport by LSEC and whether inhibition of endothelial chemokine presentation influences autoimmune hepatitis.

Methods: In the model of Concanavalin (Con) A-induced T-cell mediated hepatitis chemokine expression was determined. Chemokine uptake was visualized by confocal microscopy and transcytosis and presentation by LSEC functionally investigated in transmigration assays. Effects of reduced endothelial chemokine presentation on the development of hepatic inflammation were monitored by alanine transaminase levels and histology.

Results: During Con A-induced hepatitis, liver expression of the pro-inflammatory chemokines CXCL9 and CXCL10 significantly increased. LSEC internalized basolateral CXCL9, CXCL10 and CXCL12 via clathrin-coated vesicles and presented these chemokines immobilized on the glycosaminoglycans heparan sulphate and chondroitin sulphate to CD4⁺ T cells, thereby increasing transmigration. Blockage of the clathrin-dependent cellular transport pathway significantly reduced endothelial chemokine internalization and consequently chemokine-dependent CD4⁺ T-cell transmigration across LSEC. Inhibition of endothelial chemokine transcytosis and presentation in vivo by administration of a clathrin inhibitor suppressed Con A-induced hepatitis by preventing tissue immigration of T cells, particularly chemokine-responding CXCR3⁺CD4⁺ T cells.

Conclusions: Intervention in endothelial chemokine transcytosis and presentation affects chemokine-dependent migration of pro-inflammatory CD4⁺ T cells into the liver, thereby counteracting development of autoimmune hepatitis. Thus, chemokine presentation by LSEC during liver inflammation might be a promising therapeutic target in hepatitis.