53 - Freie Mitteilung
Inflammation & transplantation
16. Mai 2019, 10:15 - 11:45, Szenario 1, 5. OG
Non-alcoholic steatohepatitis impairs Kupffer cell-mediated immune tolerance in the mouse liver
L. A. Orci, M. Kreutzfeldt, N. Goossens, L. Rubbia-Brandt, F. Slits, V. Delaune, G. Oldani, C. Gonelle-Gispert, L. Bühler, C. Toso, S. Lacotte, Presenter: S. Lacotte (Geneva)
Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a threat to human health. Although our understanding of NAFLD pathogenesis is improving, there is limited data on the function of resident Kupffer cells in this context, especially when considering their contribution to hepatic immune tolerogenicity.
By using a unique isolation procedure, primary Kupffer cells, and not infiltrating liver monocytes, were studied in a mouse model of prolonged diet-induced liver steatohepatitis. We assessed Kupffer cell phenotype upon exposure to lipopolysaccharide or interleukin 4. We characterized Kupffer cell co-stimulation molecules expression, and did both phagocytosis and antigen presentation assays to investigate Kupffer cell function as scavenger cells and immune response initiators. We further assessed, by immunofluorescence, the expression of class II MHC and programmed-death ligand 1 (PD-L1) molecules in human liver specimens of 30 patients with increasingly severe NAFLD/NASH lesions.
Primary Kupffer cells circumscribed endotoxin-mediated inflammatory response by up-regulating anti-inflammatory genes such as arginase 1 and interleukin-10 (IL-10). Both in humans and mice, within chronically inflamed livers, Kupffer cells acquired immunomodulatory properties by reducing the expression of class II major histocompatibility complex (MHC), and by enhancing co-inhibitory signalling. While Kupffer cells isolated from mice with normal livers were capable of achieving endotoxin tolerance, our results indicated an impairment of this protective mechanism in the presence NASH-like parenchymal abnormalities. Consistent with these findings, human livers with increasingly severe NAFLD/NASH lesions displayed a decrease in class II MHC expression and an increase in PD-L1 expression, respectively.
Primary Kupffer cells are capable of achieving endotoxin tolerance, but in the chronically-inflamed fatty liver, although they acquire immunomodulatory phenotype, Kupffer cells are not sufficient to dampen immune-mediated damage. Therefore, loss of tolerance induced by ongoing liver insult may be a mechanism contributing to the worsening of NAFLD.