Department of Biomedical Science, Hallym University, Chuncheon, 24252, Republic of Korea.
Program of Material Science for Medicine and Pharmaceutics, Hallym University, Chuncheon, 24252, Republic of Korea.
J Neuroinflammation. 2024 Oct 4;21(1):250. doi: 10.1186/s12974-024-03244-y.
IL-2 regulates T cell differentiation: low-dose IL-2 induces immunoregulatory Treg differentiation, while high-dose IL-2 acts as a potent activator of cytotoxic T cells and NK cells. Therefore, high-dose IL-2 has been studied for use in cancer immunotherapy. We aimed to utilize low-dose IL-2 to treat inflammatory diseases such as obesity and insulin resistance, which involve low-grade chronic inflammation.
Systemic administration of low-dose IL-2 increased Treg cells and decreased inflammation in gonadal white adipose tissue (gWAT), leading to improved insulin sensitivity in high-fat diet-fed obese mice. Additionally, central administration of IL-2 significantly enhanced insulin sensitivity through the activation of the sympathetic nervous system. The sympathetic signaling induced by central IL-2 administration not only decreased interferon γ (IFNγ) + Th1 cells and the expression of pro-inflammatory cytokines, including Il-1β, Il-6, and Il-8, but also increased CD4 + CD25 + FoxP3 + Treg cells and Tgfβ expression in the gWAT of obese mice. These phenomena were accompanied by hypothalamic microgliosis and activation of pro-opiomelanocortin neurons. Furthermore, sympathetic denervation in gWAT reversed the enhanced insulin sensitivity and immune cell polarization induced by central IL-2 administration.
Overall, we demonstrated that IL-2 improves insulin sensitivity through two mechanisms: direct action on CD4 + T cells and via the neuro-immune axis triggered by hypothalamic microgliosis.
IL-2 调节 T 细胞分化：低剂量 IL-2 诱导免疫调节性 Treg 分化，而高剂量 IL-2 作为细胞毒性 T 细胞和 NK 细胞的有效激活剂。因此，高剂量 IL-2 已被用于癌症免疫治疗的研究。我们旨在利用低剂量 IL-2 治疗肥胖症和胰岛素抵抗等炎症性疾病，这些疾病涉及低度慢性炎症。
全身给予低剂量 IL-2 可增加 Treg 细胞并减少生殖白色脂肪组织（gWAT）中的炎症，从而改善高脂肪饮食喂养的肥胖小鼠的胰岛素敏感性。此外，IL-2 的中枢给药显著增强了胰岛素敏感性，通过激活交感神经系统。中央 IL-2 给药诱导的交感信号不仅减少了干扰素 γ（IFNγ）+Th1 细胞和促炎细胞因子（包括 Il-1β、Il-6 和 Il-8）的表达，还增加了肥胖小鼠 gWAT 中的 CD4+CD25+FoxP3+Treg 细胞和 Tgfβ 的表达。这些现象伴随着下丘脑小胶质细胞增生和 pro-opiomelanocortin 神经元的激活。此外，gWAT 中的交感神经去神经支配逆转了中枢 IL-2 给药诱导的增强的胰岛素敏感性和免疫细胞极化。
总之，我们证明了 IL-2 通过两种机制改善胰岛素敏感性：直接作用于 CD4+T 细胞和通过下丘脑小胶质细胞激活触发的神经免疫轴。
