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

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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.

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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.

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Authors and Affiliations

  1. Department of Biology, Kutztown University of Pennsylvania, Kutztown, PA, 19530, USA

    Angelika Antoni, Lee H. Graham & Cristen L. Rosch

  2. Section of Nephrology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Vimal A. Patel, Hanli Fan, Daniel J. Lee & Jerrold S. Levine

  3. Department of Computer Science, Kutztown University of Pennsylvania, Kutztown, PA, 19530, USA

    Daniel S. Spiegel

  4. Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, QC, H3G 1A4, Canada

    Joyce Rauch

  5. Section of Nephrology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, 60612, USA

    Jerrold S. Levine

  6. Section of Nephrology, University of Illinois at Chicago, MC-793, Room 479/CSN, 820 South Wood Street, Chicago, IL, 60612, USA

    Jerrold S. Levine

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  1. Angelika Antoni
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  2. Vimal A. Patel
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  9. Jerrold S. Levine
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Correspondence to Jerrold S. Levine.

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Antoni, A., Patel, V.A., Fan, H. et al. Macrophages from lupus-prone MRL mice have a conditional signaling abnormality that leads to dysregulated expression of numerous genes. Immunogenetics 63, 291–308 (2011). https://doi.org/10.1007/s00251-010-0507-3

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