Erlandsson Malin C, Malmhäll-Bah Eric, Chandrasekaran Venkataragavan, Andersson Karin M E, Nilsson Lisa M, Töyrä Silfverswärd Sofia, Pullerits Rille, Bokarewa Maria I
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, 41346 Gothenburg, Sweden.
Rheumatology Clinic, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden.
Cells. 2024 Dec 22;13(24):2124. doi: 10.3390/cells13242124.
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.
高胰岛素血症将肥胖、不良脂质谱与2型糖尿病（T2D）联系起来。在此，我们研究了胰岛素暴露对类风湿关节炎（RA）典型自身免疫中T细胞功能的影响。我们观察到胰岛素水平与CD4+细胞的糖酵解指数相关，但抑制了胰岛素受体底物的转录，这与胰岛素敏感性呈负相关。在健康对照的CD4+细胞中未观察到胰岛素水平与糖酵解指数之间的这种联系。将CD4+细胞暴露于胰岛素会诱导一种衰老状态，通过流式细胞术测量可发现细胞周期停滞和DNA含量增加。这还导致DNA损伤标志物γH2AX的积累。胰岛素抑制CD4+细胞培养物和高胰岛素血症患者中IFNγ的产生，并诱导衰老相关分泌组。抑制JAK-STAT信号传导（JAKi）可改善胰岛素信号传导，激活CD4+细胞培养物中的糖酵解指数并促进衰老。使用JAKi治疗与RA患者循环中大量的幼稚和近期胸腺迁出T细胞有关。因此，我们得出结论，胰岛素通过诱导CD4+细胞衰老和抑制IFNγ产生发挥免疫抑制作用。JAKi促进胰岛素作用并支持清除RA患者中的致病性CD4+细胞。
