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Immunogenetics

, Volume 63, Issue 5, pp 291–308 | Cite as

Macrophages from lupus-prone MRL mice have a conditional signaling abnormality that leads to dysregulated expression of numerous genes

  • Angelika Antoni
  • Vimal A. Patel
  • Hanli Fan
  • Daniel J. Lee
  • Lee H. Graham
  • Cristen L. Rosch
  • Daniel S. Spiegel
  • Joyce Rauch
  • Jerrold S. LevineEmail author
Original Paper

Abstract

Macrophages (mϕ) from pre-diseased mice of the major murine inbred models of spontaneous autoimmunity (AI), including multiple lupus-prone strains and the type I diabetes-prone NOD (non-obese diabetic) strain, have identical apoptotic target-dependent abnormalities. This characteristic feature of mϕ from AI-prone mice suggests that abnormal signaling events induced within mϕ following their interaction with apoptotic targets may predispose to AI. Such signaling abnormalities would affect predominantly the processing and presentation of self-antigen (i.e., derived from apoptotic targets), while sparing the processing and presentation of foreign antigen (i.e., derived from non-apoptotic sources). Here, we used DNA microarrays to test the hypothesis that mϕ from AI-prone mice (MRL/MpJ [MRL/+] or MRL/MpJ-Tnfrsf6 lpr [MRL/lpr]) differentially express multiple genes in comparison to non-AI mϕ (BALB/c), but do so in a largely apoptotic cell-dependent manner. Mϕ were stimulated with lipopolysaccharide, a potent innate stimulus, in the presence or absence of serum (an experimental surrogate for apoptotic targets). In accord with our hypothesis, the number of genes differentially expressed by MRL mϕ was significantly increased in the presence vs. the absence of serum, the apoptotic target surrogate (n = 401 vs. n = 201). Notably, for genes differentially expressed by MRL mϕ in the presence of serum, serum-free culture normalized their expression to a level statistically indistinguishable from that by non-AI mϕ. Comparisons of mϕ from AI-prone NOD and non-AI C57BL/6 mice corroborated these findings. Together, these data support the hypothesis that mϕ from MRL and other AI-prone mice are characterized by a conditional abnormality elicited by serum lipids or apoptotic targets.

Keywords

Rodent Autoimmunity Lupus Macrophage Diabetes Apoptosis 

Notes

Acknowledgments

This work was supported by: National Institutes of Health grants DK59793 (to JSL) and HL69722 (to JSL); National Institutes of Health training grant T32DK07510 (to AA); Canadian Institute of Health Research grants MOP-42391 (to JR) and MOP-67101 (to JR); and a Genzyme Renal Innovation Program award from Genzyme, Inc (to JSL). The authors thank the University of Chicago Functional Genomics Facility, headed by Richard Quigg, and especially Xinmin Li, Jaejung Kim, Jamie Zhou, Chris Dyanov, and Miglena Petkova, for cRNA labeling and hybridization.

Supplementary material

251_2010_507_MOESM1_ESM.pdf (487 kb)
ESM 1 (PDF 486 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Angelika Antoni
    • 1
  • Vimal A. Patel
    • 2
  • Hanli Fan
    • 2
  • Daniel J. Lee
    • 2
  • Lee H. Graham
    • 1
  • Cristen L. Rosch
    • 1
  • Daniel S. Spiegel
    • 3
  • Joyce Rauch
    • 4
  • Jerrold S. Levine
    • 2
    • 5
    • 6
    Email author
  1. 1.Department of BiologyKutztown University of PennsylvaniaKutztownUSA
  2. 2.Section of Nephrology, Department of MedicineUniversity of Illinois at ChicagoChicagoUSA
  3. 3.Department of Computer ScienceKutztown University of PennsylvaniaKutztownUSA
  4. 4.Division of Rheumatology, Department of MedicineResearch Institute of the McGill University Health CentreMontrealCanada
  5. 5.Section of Nephrology, Department of MedicineJesse Brown Veterans Affairs Medical CenterChicagoUSA
  6. 6.Section of NephrologyUniversity of Illinois at ChicagoChicagoUSA

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