FIGURE 2.

The anti-inflammatory and pro-inflammatory effects of LSECs in NAFLD. In the early stage of NAFLD, LSECs develop an anti-inflammatory phenotype manifested by the decreased expression of chemokines CCL2, CXCL10, and CXCL16 through MAPK signaling-dependent manner. LSECs can also promote the secretion of IL-10 by Th1 cells via releasing Notch ligands to exert anti-inflammatory effects. While LSECs characterized as pro-inflammatory phenotype, increase expression of adhesion factors including VCAM-1, ICAM-1, E-selectin, CD31, and VAP-1, leading to increased recruitment of leukocytes. The deficiency of autophagy also leads to up-regulation of adhesion factors and chemokines. Pro-inflammatory mediators released by LSECs, such as TNF-α, IL-1, and IL-6, also promote the progress of inflammation. The reduction of NO bioavailability contributes to the activation of KCs and the recruitment of bone marrow-derived macrophages. The hyaluronan densely coated on the surface of LSECs facilitates the recruitment of neutrophils by interacting with CD44. In addition, hepatocyte-derived EVs contribute to the recruitment of macrophages into the hepatic sinusoids. CCL C-C motif chemokine ligand, CCR C-C motif chemokine receptor, CXCL C-X-C motif chemokine ligand, eNOS endothelial nitric oxide synthase, ICAM-1 intercellular adhesion molecule-1, IL interleukin, LSEC liver sinusoidal endothelial cell, NO Nitric oxide, TNF-α tumor necrosis factor-α, VAP-1 vascular adhesion protein-1, VCAM-1 vascular cell adhesion molecule-1.