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. 2022 Aug 12;11(16):2511. doi: 10.3390/cells11162511

Figure 2.

Figure 2

The LSECs’ anti-inflammatory and pro-inflammatory profiles during the progression of NAFLDAt the early stage of NAFLD, LSECs display an anti-inflammatory function characterized by a reduced expression of chemokines such as CCL2, CXCL10, and CXCL16 through MAPK signaling and an induced expression of IL-10 by Th1 cells through the activation of Notch signaling. The activation of Notch signaling manifests anti-inflammatory effects through the induction of eNOS/sGC levels.During the progression of NAFLD from simple steatosis to NASH and cirrhosis, LSECs exhibit a pro-inflammatory phenotype mediated mostly through the activation of the NF-kB pathway. NF-kB regulates the expression of adhesion molecules (VCAM-1, ICAM-1, E-selectin, and VAP-1) as well as the secretion of pro-inflammatory cytokines (TNF-α, IL-1, and IL-6). The secretion of inflammatory mediators is also regulated by TLRs and NO bioavailability. Elevated expression of adhesion molecules leads to induced leukocyte recruitment and their translocation into the hepatic parenchyma. On the other hand, increased expression of inflammatory mediators along with LSEC dysfunction stimulates the activation of KCs and leukocyte chemoattraction. The impaired LSEC autophagy observed during the progression of NAFLD also leads to the upregulation of adhesion molecule and chemokine expression, enhancing the inflammatory response. Reduced eNOS and increased iNOS contribute to the development of inflammation, the activation of KCs, and the recruitment of bone-marrow-derived macrophages. Abbreviations: ICAM-1: Intercellular adhesion molecule-1; IL-1: Interleukin 1; IL-6: Interleukin 6; LSECs: Liver sinusoidal endothelial cells; MCP1: Monocyte chemoattractant protein-1; NF-kB: Nuclear factor kappa B; NO: nitric oxide; TNFa: Tumor necrosis factor alpha; VAP-1: Vascular adhesion protein1; VCAM-1: Vascular cell adhesion molecule-1; BMMs: bone-marrow-derived macrophages; TLR: Toll-like receptor; CXCL12: C-X-C motif chemokine ligand 12; CXCR4: C-X-C chemokine receptor type 4; KC: Kupffer cells. This image was derived from the free medical site http://smart.servier.com/ (accessed on 1 July 2022) by Servier, licensed under a Creative Commons Attribution 3.0 Unported license.