Abstract
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.
Highlights
Iron homeostasis is an essential biological process that ensures the tissue distribution of iron for various cellular processes
Α-GalCer treatment led to a significant increase in liver and spleen weights, peaking at day 3 (Fig. 1A). This is in line with a robust invariant natural killer T (iNKT) cell activation, leading to immune cell recruitment and p roliferation18,19. iNKT cell activation impacted iron metabolism
Our work suggests that iNKT activation has particular effects in iron homeostasis that could be relevant for treatments aimed at regulating hepcidin expression
Summary
Iron homeostasis is an essential biological process that ensures the tissue distribution of iron for various cellular processes. 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 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. Our results indicate that iNKT cell activation induces profound alterations in iron homeostasis
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