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Molecular Profiling of NOD mice reveals a novel regulator of insulitin onset

ABSTRACT: Non-obese Diabetes (NOD) mice are an established spontaneous model for Type 1 Diabetes (T1D), emulating diabetes development through insulitis. Using next generation sequencing, coupled with pathways analysis, the molecular fingerprint of early insulitis was mapped in a cohort of mice ranging from four to 12 weeks of age. The resulted dynamic timeline revealed an initial decrease in proliferative capacity followed by the emergence of an inflammatory signature between 6- and 8-weeks, that increases to a regulatory plateau between 10- and 12-weeks. The inflammatory signature is identified by activation of central immunogenic factors such as Infg, Il1b, Tnfa, and activation of canonical inflammatory signalling. Prodding of the regulatory landscape identified the transcription factor Atf3 as a potential novel regulator of inflammatory signalling in the NOD Islet. Furthermore, the Hedgehog (Hh) signaling pathway correlated with Atf3 regulation, hinting at role for the two in regulating the inflamed islet, however, further studies are needed to establish the nature of this connection.

ORGANISM(S): Mus musculus

PROVIDER: GSE256150 | GEO | 2024/07/03

REPOSITORIES: GEO

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Project description:Type 1 diabetes is a multigenic disease caused by T-cell mediated destruction of the insulin producing β-cells. Although conventional (targeted) approaches of identifying causative genes have advanced our knowledge of this disease, many questions remain unanswered. Using a whole molecular systems study, we unraveled the genes/molecular pathways that are altered in CD4 T-cells from young NOD mice prior to insulitis (lymphocytic infiltration into the pancreas). Many of the CD4 T-cell altered genes lie within known diabetes susceptibility regions (Idd), including several genes in the diabetes resistance region Idd13 and two genes (Khdrbs1 and Ptp4a2) in the CD4 T-cell diabetogenic activity region Idd9/11. Alterations involved apoptosis/cell proliferation and metabolic pathways (predominant at 2 weeks), inflammation and cell signaling/activation (predominant at 3 weeks), and innate and adaptive immune responses (predominant at 4 weeks). We identified several factors that may regulate these abnormalities: IRF-1, HNF4A, TP53, BCL2L1 (lies within Idd13), IFNG, IL4, IL15, and prostaglandin E2, which were common to all 3 ages; AR and IL6 to 2 and 4 weeks; and Interferon (IFN-I) and IRF-7 to 3 and 4 weeks. Others were unique to the various ages (e. g. MYC, JUN, and APP to 2 weeks; TNF, TGFB1, NFKB, ERK, and p38MAPK to 3 weeks; and IL12 and STAT4 to 4 weeks). Our data suggest that diabetes resistance genes in Idd13 and Idd9/11, and BCL2L1, IL6-AR and IFNG-IRF-1-IFN-I/IRF-7-IL12 pathways play an important role in CD4 T-cells in the early pathogenesis of autoimmune diabetes. Thus, the alternative approach of investigation at the molecular systems level has captured new information, which combined with validation studies, offers the opportunity to test hypotheses on the role played by the genes/molecular pathways identified in this study, to understand better the mechanisms of autoimmune diabetes in CD4 T-cells, and to develop new therapeutic strategies for the disease. CD4 T-cells were purified from spleen leukocytes collected from 2-, 3- and 4-week old NOD mice and two age-matched control strains, NOR, and C57BL/6, (n=5 for each strain and each age group; except NOD2wk). NOR is an insulitis- and diabetes-free control strain that shares shares ~88% of its genome with NOD mice, including the diabetogenic H2g7 MHC haplotype and several important non-MHC T1D susceptibility loci. C57BL/6 is also a diabetes-resitant strain, but it is more genetically distantly related to NOD.

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Molecular Profiling of NOD mice reveals a novel regulator of insulitin onset

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