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Cells
Volume 13
Issue 24
10.3390/cells13242124
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Article

Insulin Sensitivity Controls Activity of Pathogenic CD4+ T Cells in Rheumatoid Arthritis

by
Malin C. Erlandsson
1,2,
Eric Malmhäll-Bah
1,
Venkataragavan Chandrasekaran
1,
Karin M. E. Andersson
1,
Lisa M. Nilsson
1,
Sofia Töyrä Silfverswärd
1,
Rille Pullerits
1,3 and
Maria I. Bokarewa
1,2,*
1
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, 41346 Gothenburg, Sweden
2
Rheumatology Clinic, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden
3
Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, 41346 Gothenburg, Sweden
*
Author to whom correspondence should be addressed.
Cells 2024, 13(24), 2124; https://doi.org/10.3390/cells13242124
Submission received: 29 November 2024 / Revised: 18 December 2024 / Accepted: 20 December 2024 / Published: 22 December 2024
(This article belongs to the Section Cellular Metabolism)
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Abstract

Hyperinsulinemia connects obesity, and a poor lipid profile, with type 2 diabetes (T2D). Here, we investigated consequences of insulin exposure for T cell function in the canonical autoimmunity of rheumatoid arthritis (RA). We observed that insulin levels correlated with the glycolytic index of CD4+ cells but suppressed transcription of insulin receptor substrates, which was inversely related to insulin sensitivity. This connection between insulin levels and the glycolytic index was not seen in CD4+ cells of healthy controls. Exposure of CD4+ cells to insulin induced a senescent state recognized by cell cycle arrest and DNA content enrichment measured by flow cytometry. It also resulted in accumulation of DNA damage marker γH2AX. Insulin suppressed IFNγ production and induced the senescence-associated secretome in CD4+ cell cultures and in patients with hyperinsulinemia. Inhibition of JAK-STAT signaling (JAKi) improved insulin signaling, which activated the glycolytic index and facilitated senescence in CD4+ cell cultures. Treatment with JAKi was associated with an abundance of naïve and recent thymic emigrant T cells in the circulation of RA patients. Thus, we concluded that insulin exerts immunosuppressive ability by inducing senescence and inhibiting IFNγ production in CD4+ cells. JAKi promotes insulin effects and supports elimination of the pathogenic CD4+ cell in RA patients.
Keywords: insulin; CD4+ cells; senescence; arthritis; interferon insulin; CD4+ cells; senescence; arthritis; interferon

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MDPI and ACS Style

Erlandsson, M.C.; Malmhäll-Bah, E.; Chandrasekaran, V.; Andersson, K.M.E.; Nilsson, L.M.; Töyrä Silfverswärd, S.; Pullerits, R.; Bokarewa, M.I. Insulin Sensitivity Controls Activity of Pathogenic CD4+ T Cells in Rheumatoid Arthritis. Cells 2024, 13, 2124. https://doi.org/10.3390/cells13242124

AMA Style

Erlandsson MC, Malmhäll-Bah E, Chandrasekaran V, Andersson KME, Nilsson LM, Töyrä Silfverswärd S, Pullerits R, Bokarewa MI. Insulin Sensitivity Controls Activity of Pathogenic CD4+ T Cells in Rheumatoid Arthritis. Cells. 2024; 13(24):2124. https://doi.org/10.3390/cells13242124

Chicago/Turabian Style

Erlandsson, Malin C., Eric Malmhäll-Bah, Venkataragavan Chandrasekaran, Karin M. E. Andersson, Lisa M. Nilsson, Sofia Töyrä Silfverswärd, Rille Pullerits, and Maria I. Bokarewa. 2024. "Insulin Sensitivity Controls Activity of Pathogenic CD4+ T Cells in Rheumatoid Arthritis" Cells 13, no. 24: 2124. https://doi.org/10.3390/cells13242124

APA Style

Erlandsson, M. C., Malmhäll-Bah, E., Chandrasekaran, V., Andersson, K. M. E., Nilsson, L. M., Töyrä Silfverswärd, S., Pullerits, R., & Bokarewa, M. I. (2024). Insulin Sensitivity Controls Activity of Pathogenic CD4+ T Cells in Rheumatoid Arthritis. Cells, 13(24), 2124. https://doi.org/10.3390/cells13242124

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