Molecular Phenotyping of Immune Cells from Young NOD Mice Reveals Abnormal Metabolic Pathways in the Early Induction Phase of Autoimmune Diabetes

Jian Wu, Dorothy N. Kakoola, Nataliya I. Lenchik, Dominic M. Desiderio, Dana R. Marshall, Ivan Gerling

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Islet leukocytic infiltration (insulitis) is first obvious at around 4 weeks of age in the NOD mouse - a model for human type 1 diabetes (T1D). The molecular events that lead to insulitis and initiate autoimmune diabetes are poorly understood. Since TID is caused by numerous genes, we hypothesized that multiple molecular pathways are altered and interact to initiate this disease. We evaluated the molecular phenotype (mRNA and protein expression) and molecular networks of ex vivo unfractionated spleen leukocytes from 2 and 4 week-old NOD mice in comparison to two control strains. Analysis of the global gene expression profiles and hierarchical clustering revealed that the majority (~90%) of the differentially expressed genes in NOD mice were repressed. Furthermore, analysis using a modern suite of multiple bioinformatics approaches identified abnormal molecular pathways that can be divided broadly into 2 categories: metabolic pathways, which were predominant at 2 weeks, and immune response pathways, which were predominant at 4 weeks. Network analysis by Ingenuity pathway analysis identified key genes/molecules that may play a role in regulating these pathways. These included five that were common to both ages (TNF, HNF4A, IL15, Progesterone, and YWHAZ), and others that were unique to 2 weeks (e.g. MYC/MYCN, TGFB1, and IL2) and to 4 weeks (e.g. IFNG, beta-estradiol, p53, NFKB, AKT, PRKCA, IL12, and HLA-C). Based on the literature, genes that may play a role in regulating metabolic pathways at 2 weeks include Myc and HNF4A, and at 4 weeks, beta-estradiol, p53, Akt, HNF4A and AR. Our data suggest that abnormalities in regulation of metabolic pathways in the immune cells of young NOD mice lead to abnormalities in the immune response pathways and as such may play a role in the initiation of autoimmune diabetes. Thus, targeting metabolism may provide novel approaches to preventing and/or treating autoimmune diabetes.

Original languageEnglish (US)
Article numbere46941
JournalPLoS One
Volume7
Issue number10
DOIs
StatePublished - Oct 11 2012

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Inbred NOD Mouse
insulin-dependent diabetes mellitus
Medical problems
Metabolic Networks and Pathways
Type 1 Diabetes Mellitus
biochemical pathways
Genes
phenotype
mice
estradiol
Estradiol
genes
immune response
cells
HLA-C Antigens
Strain control
Interleukin-15
Interleukin-12
Bioinformatics
Electric network analysis

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Molecular Phenotyping of Immune Cells from Young NOD Mice Reveals Abnormal Metabolic Pathways in the Early Induction Phase of Autoimmune Diabetes. / Wu, Jian; Kakoola, Dorothy N.; Lenchik, Nataliya I.; Desiderio, Dominic M.; Marshall, Dana R.; Gerling, Ivan.

In: PLoS One, Vol. 7, No. 10, e46941, 11.10.2012.

Research output: Contribution to journalArticle

Wu, Jian ; Kakoola, Dorothy N. ; Lenchik, Nataliya I. ; Desiderio, Dominic M. ; Marshall, Dana R. ; Gerling, Ivan. / Molecular Phenotyping of Immune Cells from Young NOD Mice Reveals Abnormal Metabolic Pathways in the Early Induction Phase of Autoimmune Diabetes. In: PLoS One. 2012 ; Vol. 7, No. 10.
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