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. 2018 Sep 11;9:2082. doi: 10.3389/fimmu.2018.02082

Figure 1.

Figure 1

A working model showing a key immune regulatory network mediated by activation of iNKT and/or type II NKT cell subsets in the control of homeostasis in liver and in the gut. iNKT activation: In most experimental models of chronic liver diseases, hepatic iNKT cells but not type II NKT cells become rapidly activated. Following feeding of choline-deficient, high fat or alcoholic diets, plasmacytoid DC (pDC) are activated by hepatocyte death and release of mitochondrial DNA. While pDC activate a subset of iNKT cells to secrete IL-17A (iNKT17), conventional DC (cDC) are involved in activation of iNKT secreting IFNγ/IL-4/IL-13 (iNKT1/2). Activation of iNKT cells mediates steatosis and steatohepatitis following recruitment of macrophage/neutrophil and fat deposition in hepatocytes. Furthermore, iNKT cells initiate and accelerate HSC activation and, consequently, fibrosis. This is also associated with increased frequency of migrating cDCs from gut that prime the conventional CD4+/CD8+ T cells and promote macrophages infiltration into liver leading to enhanced liver damage. Additionally, activated iNKT cells can also express FasL and kill directly Fas-expressing and CD1d+ hepatocytes. Similarly, in the gut, following chronic feeding of these diets, the microbiota and lipid profiles are altered resulting in activation of iNKT cells mediated by CD1d+ intestinal epithelial cells and/or migratory cDCs. Thus, activated iNKT cells migrate into the liver via portal vein and contribute to liver injury. Type II NKT activation: administration of sulfatide and LPC results in activation of hepatic type II NKT cells that cross-regulate iNKT cell-mediated inflammatory cascade and inhibits chronic liver diseases, including ASH and NAFLD. LPC, lysophosphatidylcholine; pDC, plasmacytoid DC; cDC, conventional DC; Mφ, macrophages; HSC, hepatic stellate cells; HFHC, high fat high carbohydrate diet; CDAA, choline deficient amino acid defined diet; ASH, alcoholic steatohepatitis; NAFLD, nonalcoholic fatty liver disease; IBD, inflammatory bowel disease.