Macrophages from lupus-prone MRL mice have a conditional signaling abnormality that leads to dysregulated expression of numerous genes |
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Authors: | Angelika Antoni Vimal A Patel Hanli Fan Daniel J Lee Lee H Graham Cristen L Rosch Daniel S Spiegel Joyce Rauch Jerrold S Levine |
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Institution: | (1) Department of Biology, Kutztown University of Pennsylvania, Kutztown, PA 19530, USA;(2) Section of Nephrology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA;(3) Department of Computer Science, Kutztown University of Pennsylvania, Kutztown, PA 19530, USA;(4) Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montreal, QC, H3G 1A4, Canada;(5) Section of Nephrology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, 60612, USA;(6) Section of Nephrology, University of Illinois at Chicago, MC-793, Room 479/CSN, 820 South Wood Street, Chicago, IL 60612, USA; |
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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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