title: Specific immunization strategies against oxidized low-density lipoprotein: a novel way to reduce nonalcoholic steatohepatitis in mice.
abstract: Nonalcoholic steatohepatitis (NASH) is characterized by hepatic lipid accumulation combined with inflammation, which can ultimately progress into cirrhosis. Recently, we demonstrated that deletion of scavenger receptors (SRs) CD36 and SR-A in hematopoietic cells reduced hepatic inflammation. In addition to uptake of modified lipoproteins, CD36 and SR-A are also involved in other functions that can activate the inflammatory response. Therefore, the actual trigger for SR activation during NASH is unclear. Here, we hypothesized that hepatic inflammation is triggered by recognition of oxidized LDL (oxLDL) by Kupffer cells (KCs). To inhibit recognition of oxLDL by KCs, low-density lipoprotein receptor (Ldlr(-/-) ) mice were immunized with heat-inactivated pneumococci, which were shown to induce the production of anti-oxLDL immunoglobulin M (IgM) antibodies, due to molecular mimicry with oxLDL. The mice received a high-fat, high-cholesterol diet during the last 3 weeks to induce NASH. Immunization with pneumococci increased anti-oxLDL IgM levels and led to a reduction in hepatic inflammation, as shown by reduced macrophage, neutrophil, and T cell infiltration, and reduced gene expression of tumor necrosis factor (Tnf), interleukin-6 (Il-6), interleukin-1β (Il-1b), monocyte chemoattractant protein 1 (Mcp1), and fibrosis-related genes. In immunized mice, KCs were smaller and showed fewer cholesterol crystals compared with nonimmunized mice.
  
  
  CONCLUSIONS
  Antibodies to oxLDL play an important role in the pathogenesis of NASH. Therefore, the potential of phosphorylcholine-based vaccination strategies as a novel tool for the prevention and therapy of NASH should be tested in the future.
authors.affiliation: Department of Molecular Genetics, Maastricht University, the Netherlands.
authors.forename: Veerle
authors.initials: V
authors.lastname: Bieghs
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: van Gorp
authors.forename: Sofie M A
authors.initials: SM
authors.lastname: Walenbergh
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Gijbels
authors.forename: Fons
authors.initials: F
authors.lastname: Verheyen
authors.forename: Wim A
authors.initials: WA
authors.lastname: Buurman
authors.forename: David E
authors.initials: DE
authors.lastname: Briles
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Binder
authors.forename: Ronit
authors.initials: R
authors.lastname: Shiri-Sverdlov
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D005234:Fatty Liver / Q000188:drug therapy / Q000276:immunology* / Q000517:prevention & control*; D007114:Immunization / Q000379:methods*; D008077:Lipoproteins, LDL / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D013296:Streptococcus pneumoniae / Q000276:immunology
chemical_list: D000906:Antibodies; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein