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| Status |
Public on May 24, 2024 |
| Title |
Microarray data, 4 week HFD/NCD, nostim or 16hrstim |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
How autoimmunity is initiated in Multiple Sclerosis (MS) is unknown, but both genetic and environmental factors have been implicated. Female physiology is associated with a three times higher risk of MS and the ratio of woman to men diagnosed with MS has been increasing over time, suggesting that environmental factors are interacting with female sex to initiate this disease. One MS risk factor that has been increasing that interacts with female sex is obesity. Being overweight or obese as an adolescent increases one’s risk of MS by 2-fold and this risk increases if one is female. To explore how obesity and female sex interact to control T helper autoimmunity, we conducted a proteomic screen on the serum of male and female healthy weight and obese participants that were affected or not affected by MS. We found that obese individuals, regardless of disease status, exhibited a prominent upregulation of proteins in pathways associated with the damage-associated S100 protein pathway, T helper 1 (Th1), IL-17 pathways and RIG-I/Interferon pathways and that this increase was more prominent in women. To explore the mechanisms of how female sex interacts with increased adiposity to regulate CNS autoimmunity, we modeled a diet-induced overweight (DIO) state in mice by placing animals on high fat diet for 4 weeks and then inducing experimental autoimmune encephalomyelitis (EAE), a model of MS. We found that DIO enhanced EAE severity in mice of both sexes compared to controls and this effect was more pronounced in female mice. The increased severity in the female DIO mice associated with a greater accumulation of pathogenic IFN-+IL-17+ CD4+ cells in the CNS and more severe tissue damage. Further studies of mice at steady-state revealed that DIO increased the frequency of CD44hiCD4+ T cells and enhanced the potential of naïve CD4+ T cells to produce IFN-This phenotype of higher T cell IFN-was also observed in female humans who were overweight. Furthermore, IFN-α was detected at significantly increased levels in the serum of the DIO-female compared to DIO-male or sex-matched control mice. Loss of IFN-α receptor in T cells negated the increases in Th1 inflammation and EAE severity caused by DIO in female mice. These results highlight that an overweight state may interact with female sex to selectively enhance Th1 responses and CNS autoimmunity by increasing type I and type I IFN signalling in T cells.
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| Overall design |
C57BL6 mice were placed on a normal chow diet (NCD) or a High fat-diet (HFD) for 4 weeks, then naïve CD4+ T cells (CD4+ CD44low-int) were magnetically isolated by negative selection from spleens and lymph nodes and stimulated with 2ug/ml plate-bound anti-CD3 and anti-CD28 antibodies for 16hrs. Total RNA was then isolated (RNEAsy, Qiagen). Total RNA quality was analyzed by RNA 6000 Pico LabChip on a 2100 BioAnalyzer (Agilent). RNA integrity numbers for samples were > 5.2. 10 ng of total RNA was reverse transcribed using GeneChip WT Pico Kit (Affymetrix). Each sample was hybridized to a GeneChip Mouse Gene 2.0 ST array (Affymetrix) for 16- 18 h at 45 °C. The arrays were scanned using a GeneChip Scanner 3000 (Affymetrix).RNA integrity analysis and microarray probing and detection were performed by the Microarray Facility of the Centre for Applied Genomics at the Hospital for Sick Children, Toronto, Canada.
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| Contributor(s) |
Cordeiro B, Ahn JJ, Gawde S, Ucciferri C, Alvarez-Sanchez N, Revelo X, Stickle N, Massey K, Brooks DG, Guthridge JM, Pardo G, Winer DA, Axtell RC, Dunn SE |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Aug 17, 2023 |
| Last update date |
May 24, 2024 |
| Contact name |
Brendan Cordeiro |
| E-mail(s) |
brendan.cordeiro@unityhealth.to
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| Organization name |
St-michael's hospital
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| Department |
Keenan Research Center
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| Lab |
Dr. Shannon Dunn
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| Street address |
209 Victoria St.
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| City |
Toronto |
| State/province |
Ontario |
| ZIP/Postal code |
M5B 1W8 |
| Country |
Canada |
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| Platforms (1) |
| GPL16570 |
[MoGene-2_0-st] Affymetrix Mouse Gene 2.0 ST Array [transcript (gene) version] |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA1006291 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE241044_RAW.tar |
163.3 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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