title: Natural killer cell-dependent anti-fibrotic pathway in liver injury via Toll-like receptor-9.
abstract: The toll-like receptor-9 (TLR9) agonist cytosine phosphate guanine (CpG), activates hepatic stellate cells (HSCs) and mediates fibrosis. We investigated the TLR9 effects on lymphocyte/HSCs interactions. Liver fibrosis was induced in wild-type (WT) mice by intra-peritoneal carbon-tetrachloride (CCl4) induction for 6 weeks. Fibrotic groups were intravenously treated by a vehicle versus CpG along last 2 weeks. Compared to vehicle-treated fibrotic WT, the in-vivo CpG-treatment significantly attenuated hepatic fibrosis and inflammation, associated with decreased CD8 and increased NK liver cells. In-vitro, co-cultures with vehicle-treated fibrotic NK cells increased HSCs proliferation (P<0.001) while their CpG-treated counterparts achieved a significant decrease. To investigate the role of lymphocytes, TLR9(-/-) mice induced-hepatic fibrosis were used. Although TLR9(-/-) mice manifested lower fibrotic profile as compared to their wild-type (WT) counterparts, senescence (SA-β-Gal activity) in the liver and ALT serum levels were significantly greater. In an adoptive transfer model; irradiated WT and TLR9(-/-) recipients were reconstituted with naïve WT or TLR9(-/-) lymphocytes. The adoptive transfer of TLR9(-/-) versus WT lymphocytes led to increased fibrosis of WT recipients. TLR9(-/-) fibrotic recipients reconstituted with TLR9(-/-) or WT lymphocytes showed no changes in hepatic fibrosis severity or ALT serum levels. TLR9 activation had inconsistent effects on lymphocytes and HSCs. The net balance of TLR9 activation in WT, displayed significant anti-fibrotic activity, accompanied by CD8 suppression and increased NK-cells, activity and adherence to HSCs. The pro-fibrotic and pro-inflammatory properties of TLR9(-/-) lymphocytes fail to activate HSCs with an early senescence in TLR9(-/-) mice.
authors: Liver & Gastroenterology Units; Division of Medicine, Hadassah Medical Center, Jerusalem, Israel.
authors: Lina
authors: L
authors: Abu-Tair
authors: Jonathan H
authors: JH
authors: Axelrod
authors: Sarit
authors: S
authors: Doron
authors: Yossi
authors: Y
authors: Ovadya
authors: Valery
authors: V
authors: Krizhanovsky
authors: Eithan
authors: E
authors: Galun
authors: Johnny
authors: J
authors: Amer
authors: Rifaat
authors: R
authors: Safadi
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002252:Carbon Tetrachloride Poisoning / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D055166:Hepatic Stellate Cells / Q000276:immunology* / Q000473:pathology; D007694:Killer Cells, Natural; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9