Fig. 3. Lymphocyte recruitment within the hepatic sinusoids.

Lymphocyte recruitment involves an adhesion cascade within the hepatic sinusoids that is influenced by the low shear environment and cellular crosstalk between parenchymal and non-parenchymal cells. Chronic parenchymal cell damage leads to the release of danger-associated molecular patterns (DAMPs) and pro-inflammatory mediators by Kupffer cells, which increase adhesion molecule expression by liver sinusoidal endothelial cells (LSECs) (step 1). Lymphocyte recruitment across activated LSECs involves a selectin-independent tethering step (step 2), followed by integrin activation and firm adhesion to immunoglobulin superfamily members on the LSEC surface (step 3). This process is influenced by paracrine factors released from hepatocytes. Lymphocytes then crawl along the luminal endothelium (step 4) until they receive a signal to transmigrate across LSECs through either a paracellular or a transcellular route (step 5). A third route of lymphocyte migration involves intracellular migration directly into the LSEC body and then migration to the adjacent LSEC, termed intracellular crawling (step 6). Release of chemotactic factors from activated hepatic stellate cells promotes subsequent migration and positioning in liver tissue (step 7). CXCR3, CXC-chemokine receptor 3; ECM, extracellular matrix; ICAM1, intercellular adhesion molecule 1; MADCAM1, mucosal addressin cell adhesion molecule 1; VAP1, vascular adhesion protein1; VCAM1, vascular cell adhesion molecule 1.