Scavenger Receptors on Sinusoidal Liver Endothelial Cells Are Involved in the Uptake of Aldehyde-Modified Proteins

Duryee, Michael J.; Freeman, Thomas L.; Willis, Monte S.; Hunter, Carlos D.; Hamilton, Bartlett C.; Suzuki, Hiroshi; Tuma, Dean J.; Klassen, Lynell Warren; Thiele, Geoffrey M.

doi:10.1124/mol.105.016121

Cited by 48 publications

(40 citation statements)

References 36 publications

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“…Further, we show that MAA-LDL is specifi cally bound by macrophage scavenger receptors ( Fig. 6A, B ) consistent with prior reports showing that other MAA-modifi ed proteins are also bound by scavenger receptors ( 35,36 ).…”

Section: Second: Maa Epitopes Are Immunodominant Structures Of the MDsupporting

confidence: 92%

Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine

Gonen

Hansen

Turner

et al. 2014

Journal of Lipid Research

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It is now widely recognized that atherosclerosis is a chronic infl ammatory disease and that immune modulation Abstract Immunization with homologous malondialdehyde (MDA)-modifi ed LDL (MDA-LDL) leads to atheroprotection in experimental models supporting the concept that a vaccine to oxidation-specifi c epitopes (OSEs) of oxidized LDL could limit atherogenesis. However, modifi cation of human LDL with OSE to use as an immunogen would be impractical for generalized use. Furthermore, when MDA is used to modify LDL, a wide variety of related MDA adducts are formed, both simple and more complex. To defi ne the relevant epitopes that would reproduce the atheroprotective effects of immunization with MDA-LDL, we sought to determine the responsible immunodominant and atheroprotective adducts. We now demonstrate that fl uorescent adducts of MDA involving the condensation of two or more MDA molecules with lysine to form malondialdehyde-acetaldehyde (MAA)-type adducts generate immunodominant epitopes that lead to atheroprotective responses. We further demonstrate that a T helper (Th ) 2-biased hapten-specifi c humoral and cellular response is suffi cient, and thus, MAA-modifi ed homologous albumin is an equally effective immunogen. We further show that such Th2-biased humoral responses per se are not atheroprotective if they do not target relevant antigens. These data demonstrate the feasibility of development of a smallmolecule immunogen that could stimulate MAA-specifi c immune responses, which could be used to develop a vaccine approach to retard or prevent atherogenesis. -Gonen, A.,

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Section: Second: Maa Epitopes Are Immunodominant Structures Of the MDsupporting

confidence: 92%

Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine

Gonen

Hansen

Turner

et al. 2014

Journal of Lipid Research

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“…Acetaldehyde has been also shown to be conjugated with numerous proteins including tubulin (Israel, 1997;Jennett, Sorrell, Saffari-Fard, Ockner, & Tuma, 1989;Niemelä et al, 1998Niemelä et al, , 1994Sutti et al, 2014) to activate immune reactions. Critical roles of ALDH2 and CYP2E1 in producing MAA or advanced glycation end product (AGE) adducts and other protein adducts have been suggested (Anderson et al, 2014;Duryee et al, 2005;Jeong et al, 2000;Kwon et al, 2014;Swaminathan, Kumar, Clemens, & Dey, 2013;Thiele et al, 2001). In addition, acetaldehyde can interact with DNA to produce DNA adducts (Brooks et al, 2009;Yu et al, 2010Yu et al, , 2012.…”

Section: Role and Regulation Of Aldh2 In Liver Diseasementioning

confidence: 99%

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

Song

Akbar

et al. 2015

Advances in Pharmacology

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“…Previous studies performed by our laboratory have shown that MAA adducted proteins bind to scavenger receptors on peritoneal macrophages, sinusoidal liver endothelial cells, and Kupffer cells [29,38,39]. It was also shown that macrophages could release pro-inflammatory cytokines in response to MAA-modified proteins [39].…”

Section: Discussionmentioning

confidence: 90%

Increased immunogenicity to P815 cells modified with malondialdehyde and acetaldehyde

Duryee¹,

Klassen²,

Jones³

et al. 2008

International Immunopharmacology

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Aldehyde modified proteins have been associated with the development and/or progression of alcoholic liver disease (ALD). These protein adducts are capable of initiating many immunological responses that are harmful to the normal homeostasis of organism function. Previous studies have shown that malondialdehyde (MDA) and acetaldehyde (AA) synergistically form a unique adduct (MAA) with soluble proteins, which are capable of inducing cytokine release, T-cell proliferation, and antibody production. The purpose of this study was to determine whether MAA adduction can elicit similar responses to cells using a well-defined tumor model. The mouse mastocytoma P815 tumor cell line was modified with MAA (P815-MAA) or left unmodified (P815) and 10(6) irradiated cells were injected into DBA/2 mice once a week for 5 weeks. Serum was collected and tested for antibody responses to P815 cells and the MAA epitope. Immunization of MAA adducted P815 cells into syngeneic DBA/2 mice induced a strong antibody response to the MAA epitope as determined by ELISA on Alb and MAA-Alb (508 microg/ml and 1092 microg/ml, respectively). In addition, antibody to unmodified P815 cells was detected by fluorescent technique. Mice immunized with P815 cells or PBS showed little or no reactivity to the MAA epitope or P815 cells. Studies to assess IL-12 stimulation showed that peritoneal macrophages from P815 and PBS immunized animals produced modest amounts of IL-12 (20 and 35 pg/ml) when stimulated with Alb or MAA-Alb. However, macrophage from P815-MAA immunized mice responded to soluble MAA adduct (142 pg/ml). Finally, in tumor survival studies the mean survival was 14.25 days in PBS treated mice; 15.75 days with P815 immunized mice and 18.25 days with P815-MAA immunized mice. Therefore, these data strongly suggest that antibody responses are induced by P815 cells modified with MAA adducts. This may be a possible tool to begin looking at how alcohol metabolites potentially modify cells and/or cellular components making them recognizable to the immune system as foreign. It is thought that these studies define a model system that will be useful in assessing antibody and potentially T-cell responses to cells that are modified by MAA.

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Scavenger Receptors on Sinusoidal Liver Endothelial Cells Are Involved in the Uptake of Aldehyde-Modified Proteins

Cited by 48 publications

References 36 publications

Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine

Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

Increased immunogenicity to P815 cells modified with malondialdehyde and acetaldehyde

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