Department of Biochemistry and Biophysics, Stockholm University, 114 Stockholm, Sweden.
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 114 Stockholm, Sweden.
Int J Mol Sci. 2023 Feb 13;24(4):3717. doi: 10.3390/ijms24043717.
Omega-3 (ω-3) polyunsaturated fatty acids, including docosahexaenoic acid (DHA), are involved in numerous biological processes and have a range of health benefits. DHA is obtained through the action of elongases (ELOVLs) and desaturases, among which Elovl2 is the key enzyme involved in its synthesis, and can be further metabolized into several mediators that regulate the resolution of inflammation. Our group has recently reported that ELOVL2 deficient mice (Elovl2) not only display reduced DHA levels in several tissues, but they also have higher pro-inflammatory responses in the brain, including the activation of innate immune cells such as macrophages. However, whether impaired synthesis of DHA affects cells of adaptive immunity, i.e., T lymphocytes, is unexplored. Here we show that Elovl2 mice have significantly higher lymphocytes in peripheral blood and that both CD8+ and CD4+ T cell subsets produce greater amounts of pro-inflammatory cytokines in both blood and spleen compared to wild type mice, with a higher percentage of cytotoxic CD8+ T cells (CTLs) as well as IFN-γ-producing Th1 and IL-17-producing Th17 CD4+ cells. Furthermore, we also found that DHA deficiency impacts the cross-talk between dendritic cells (DC) and T cells, inasmuch as mature DCs of Elovl2 mice bear higher expression of activation markers (CD80, CD86 and MHC-II) and enhance the polarization of Th1 and Th17 cells. Reintroducing DHA back into the diets of Elovl2 mice reversed the exacerbated immune responses observed in T cells. Hence, impairment of endogenous synthesis of DHA exacerbates T cell inflammatory responses, accounting for an important role of DHA in regulating adaptive immunity and in potentially counteracting T-cell-mediated chronic inflammation or autoimmunity.
ω-3 多不饱和脂肪酸，包括二十二碳六烯酸（DHA），参与多种生物过程，并具有广泛的健康益处。DHA 通过延长酶（ELOVLs）和去饱和酶的作用获得，其中 Elovl2 是参与其合成的关键酶，并且可以进一步代谢为几种调节炎症消退的介质。我们的研究小组最近报道，ELOVL2 缺陷小鼠（Elovl2）不仅在几种组织中显示 DHA 水平降低，而且在大脑中还具有更高的促炎反应，包括先天免疫细胞如巨噬细胞的激活。然而，DHA 合成受损是否会影响适应性免疫细胞，即 T 淋巴细胞，尚未得到探索。在这里，我们显示 Elovl2 小鼠在外周血中有显著更高的淋巴细胞，并且 CD8+和 CD4+T 细胞亚群在血液和脾脏中产生更多的促炎细胞因子，具有更高比例的细胞毒性 CD8+T 细胞（CTL）以及 IFN-γ 产生的 Th1 和 IL-17 产生的 Th17 CD4+细胞。此外，我们还发现 DHA 缺乏会影响树突状细胞（DC）和 T 细胞之间的串扰，因为 Elovl2 小鼠的成熟 DC 具有更高的激活标志物（CD80、CD86 和 MHC-II）表达，并增强了 Th1 和 Th17 细胞的极化。将 DHA 重新引入 Elovl2 小鼠的饮食中，逆转了 T 细胞中观察到的过度免疫反应。因此，内源性 DHA 合成的受损加剧了 T 细胞炎症反应，这表明 DHA 在调节适应性免疫以及潜在地对抗 T 细胞介导的慢性炎症或自身免疫方面发挥着重要作用。
