Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
Département de Médecine, Université de Montréal, Montréal, Québec, Canada.
Sci Rep. 2020 Dec 3;10(1):21026. doi: 10.1038/s41598-020-78037-3.
Iron homeostasis is an essential biological process that ensures the tissue distribution of iron for various cellular processes. As the major producer of hepcidin, the liver is central to the regulation of iron metabolism. The liver is also home to many immune cells, which upon activation may greatly impact iron metabolism. Here, we focus on the role of invariant natural killer T (iNKT) cells, a subset of T lymphocytes that, in mice, is most abundant in the liver. Activation of iNKT cells with the prototypical glycosphingolipid antigen, α-galactosylceramide, resulted in immune cell proliferation and biphasic changes in iron metabolism. This involved an early phase characterized by hypoferremia, hepcidin induction and ferroportin suppression, and a second phase associated with strong suppression of hepcidin despite elevated levels of circulating and tissue iron. We further show that these changes in iron metabolism are fully dependent on iNKT cell activation. Finally, we demonstrate that the biphasic regulation of hepcidin is independent of NK and Kupffer cells, and is initially driven by the STAT3 inflammatory pathway, whereas the second phase is regulated by repression of the BMP/SMAD signaling pathway. These findings indicate that iNKT activation and the resulting cell proliferation influence iron homeostasis.
铁稳态是一种基本的生物学过程，可确保铁在各种细胞过程中的组织分布。肝脏是产生铁调素的主要器官，是铁代谢调节的核心。肝脏也是许多免疫细胞的所在地，这些免疫细胞在被激活后可能会极大地影响铁代谢。在这里，我们重点关注固有自然杀伤 T(iNKT)细胞的作用，iNKT 细胞是 T 淋巴细胞的一个亚群，在小鼠中，肝脏中 iNKT 细胞最为丰富。用原型糖脂抗原α-半乳糖基鞘氨醇激活 iNKT 细胞会导致免疫细胞增殖和铁代谢的双相变化。这涉及到一个早期阶段，其特征是低血症、铁调素诱导和铁蛋白抑制，以及第二个阶段，尽管循环和组织铁水平升高，但强烈抑制铁调素。我们进一步表明，这些铁代谢的变化完全依赖于 iNKT 细胞的激活。最后，我们证明铁调素的双相调节独立于 NK 和枯否细胞，最初由 STAT3 炎症途径驱动，而第二阶段则由 BMP/SMAD 信号通路的抑制调节。这些发现表明，iNKT 激活和由此产生的细胞增殖会影响铁稳态。
