Malondialdehyde-acetaldehyde haptenated protein binds macrophage scavenger receptor(s) and induces lysosomal damage

Monte S. Willis, Lynell W. Klassen, Deborah L. Carlson, Chad F. Brouse, Geoffrey M. Thiele

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

There is evidence that the chemical modification of proteins (haptens) with malondialdehyde-acetaldehyde (MAA) and the immune response to these haptenated proteins is associated with the initiation and/or progression of alcohol liver disease. Experimentally, proteins modified with MAA induce antibody and T cell responses, which are mediated by scavenger receptor(s). Moreover, macrophages have been shown to play an important role in processing and presenting MAA-haptenated proteins in vitro. In vitro, MAA-modified proteins have been shown to induce both apoptosis and necrosis in a dose- and cell-type-dependent manner. Natural ligands modified by oxidative stress, such as oxidized LDL, similarly initiate not only antibody responses, but also cause cell death by disrupting lysosomes after binding to scavenger receptors and internalization. We therefore investigated the binding, internalization, and lysosomal integrity in a macrophage cell line to a MAA-haptenated protein. We demonstrate for the first time that MAA-haptenated proteins are preferentially bound by scavenger receptors on macrophages, which internalize the ligands and shuttle them to lysosomes. Moreover, MAA-haptenated proteins are demonstrated to be associated with a rapid dose-dependent disruption in lysosomal integrity, resulting in leakage and caspase activation. Similarly, as hen egg lysozyme (HEL)-MAA concentrations increased (>31.3 μg/ml), increased levels of apoptosis and a G1/S cell cycle checkpoint inhibition were identified. This study identifies mechanisms by which MAA-haptenated proteins are taken up by a representative antigen-presenting cell and may delineate steps by which MAA-haptenated proteins induce cell death and induce their immunogenicity to the carrier protein.

Original languageEnglish (US)
Pages (from-to)885-899
Number of pages15
JournalInternational Immunopharmacology
Volume4
Issue number7
DOIs
StatePublished - Jul 2004

Keywords

  • AA
  • AO
  • Acetaldehyde
  • Cell death
  • DTPA
  • Geometric mean
  • HEL
  • Lysosomal damage
  • MAA
  • MDA
  • Malondialdehyde
  • Oxidative stress
  • acetaldehyde
  • acridine orange
  • diethylenetriamine-pentaacetic acid
  • geometric mean fluorescence
  • hen egg lysozyme
  • malondialdehyde

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

Fingerprint Dive into the research topics of 'Malondialdehyde-acetaldehyde haptenated protein binds macrophage scavenger receptor(s) and induces lysosomal damage'. Together they form a unique fingerprint.

  • Cite this