Specific immunization strategies against oxidized... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

Specific immunization strategies against oxidized low-density lipoprotein: A novel way to reduce nonalcoholic steatohepatitis in mice

Bieghs, Veerle1; van Gorp, Patrick J.1; Walenbergh, Sofie M.A.1; Gijbels, Marion J.1,2; Verheyen, Fons3; Buurman, Wim A.4; Briles, David E.5,6; Hofker, Marten H.7; Binder, Christoph J.8,9; Shiri-Sverdlov, Ronit1,*

1_Departments of Molecular Genetics, Maastricht University, the Netherlands_

2_Pathology, Maastricht University, the Netherlands_

3_Molecular Cell Biology, Electron Microscopy Unit, Maastricht University, the Netherlands_

4_Surgery, Maastricht University, the Netherlands_

5_Departments of Microbiology, The University of Alabama at Birmingham, Birmingham, AL_

6_Departments of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL_

7_Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands_

8_Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria_

9_Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria_

*Address reprint requests to: Department of Molecular Genetics, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands

Email:[email protected]

Accepted 6 February 2011; Received 3 September 2011

Potential conflict of interest: Nothing to report.

Supported by Veni 916.76.070 (grant 2006/00496/MW), Maag Lever Darm Stichting (grants WO 08–16 and WO 09–46), and the National Institutes of Health (grant R01 AI21548).

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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. Conclusion: 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.