Diff erential oxidative modifi cation of proteins in MRL +/+ and MRL/lpr mice: Increased formation of lipid peroxidation-derived aldehyde-protein adducts may contribute to accelerated onset of autoimmune response

Gangduo Wang, Hui Li, M. Firoze Khan

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Even though reactive oxygen species (ROS) have been implicated in SLE pathogenesis, the contributory role of ROS, especially the consequences of oxidative modifi cation of proteins by lipid peroxidation-derived aldehydes (LPDAs) such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE) in eliciting an autoimmune response and disease pathogenesis remains largely unexplored. MRL/lpr mice, a widely used model for SLE, spontaneously develop a condition similar to human SLE, whereas MRL+/+ mice with the same MRL background, show much slower onset of SLE. To assess if the diff erences in the onset of SLE in the two substrains could partly be due to diff erential expression of LPDAs and to provide evidence for the role of LPDA-modifi ed proteins in SLE pathogenesis, we determined the serum levels of MDA-/HNE-protein adducts, anti-MDA-/HNE-protein adduct antibodies, MDA-/HNE-protein adduct specifi c immune complexes, and various autoantibodies in 6-, 12-and 18-week old mice of both substrains. The results show age-related increases in the formation of MDA-/HNE-protein adducts, their corresponding antibodies and MDA-/HNE-specifi c immune complexes, but MRL/lpr mice showed greater and more accelerated response. Interestingly, a highly positive correlation between increased anti-MDA-/HNE-protein adduct antibodies and autoantibodies was observed. More importantly, we further observed that HNE-MSA caused signifi cant inhibition in antinuclear antibodies (ANA) binding to nuclear antigens. These fi ndings suggest that LPDA-modifi ed proteins could be important sources of autoantibodies and CICs in these mice, and thus contribute to autoimmune disease pathogenesis. The observed diff erential responses to LPDAs in MRL/lpr and MRL+/+ mice may, in part, be responsible for accelerated and delayed onset of the disease, respectively.

Original languageEnglish (US)
Pages (from-to)1472-1481
Number of pages10
JournalFree Radical Research
Volume46
Issue number12
DOIs
StatePublished - Dec 2012

Keywords

  • 4-hydroxynonenal
  • autoantibodies
  • lipid peroxidation
  • malondialdehyde
  • protein adducts

ASJC Scopus subject areas

  • Biochemistry

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