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

20 Citations (Scopus)

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

Fingerprint

Scavenger Receptors
Acetaldehyde
Malondialdehyde
Proteins
Lysosomes
Cell Death
Macrophages
Apoptosis
Ligands
G1 Phase Cell Cycle Checkpoints
Haptens
Antigen-Presenting Cells
Caspases
Antibody Formation
Liver Diseases
Cause of Death
Carrier Proteins
Oxidative Stress
Necrosis
Alcohols

Keywords

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

ASJC Scopus subject areas

  • Immunology
  • Pharmacology

Cite this

Malondialdehyde-acetaldehyde haptenated protein binds macrophage scavenger receptor(s) and induces lysosomal damage. / Willis, Monte S.; Klassen, Lynell W.; Carlson, Deborah L.; Brouse, Chad F.; Thiele, Geoffrey M.

In: International Immunopharmacology, Vol. 4, No. 7, 07.2004, p. 885-899.

Research output: Contribution to journalArticle

Willis, Monte S. ; Klassen, Lynell W. ; Carlson, Deborah L. ; Brouse, Chad F. ; Thiele, Geoffrey M. / Malondialdehyde-acetaldehyde haptenated protein binds macrophage scavenger receptor(s) and induces lysosomal damage. In: International Immunopharmacology. 2004 ; Vol. 4, No. 7. pp. 885-899.
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T1 - Malondialdehyde-acetaldehyde haptenated protein binds macrophage scavenger receptor(s) and induces lysosomal damage

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AU - Klassen, Lynell W.

AU - Carlson, Deborah L.

AU - Brouse, Chad F.

AU - Thiele, Geoffrey M.

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N2 - 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.

AB - 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.

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KW - AO

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KW - Geometric mean

KW - geometric mean fluorescence

KW - HEL

KW - hen egg lysozyme

KW - Lysosomal damage

KW - MAA

KW - Malondialdehyde

KW - malondialdehyde

KW - MDA

KW - Oxidative stress

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