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Acute invariant NKT cell activation triggers an immune response that drives prominent changes in iron homeostasis.

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, ?-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.

SUBMITTER: Huang H

PROVIDER: S-EPMC7713400 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Acute invariant NKT cell activation triggers an immune response that drives prominent changes in iron homeostasis.

Huang Hua H Zuzarte-Luis Vanessa V Fragoso Gabriela G Calvé Annie A Hoang Tuan Anh TA Oliero Manon M Chabot-Roy Geneviève G Mullins-Dansereau Victor V Lesage Sylvie S Santos Manuela M MM

Scientific reports 20201203 1

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 t ...[more]

PMID: 33273556

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Project description:Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. Although intra-amniotic infection is a recognized cause of spontaneous preterm labor, the noninfection-related etiologies are poorly understood. In this article, we demonstrated that the expansion of activated CD1d-restricted invariant NKT (iNKT) cells in the third trimester by administration of ?-galactosylceramide (?-GalCer) induced late PTB and neonatal mortality. In vivo imaging revealed that fetuses from mice that underwent ?-GalCer-induced late PTB had bradycardia and died shortly after delivery. Yet, administration of ?-GalCer in the second trimester did not cause pregnancy loss. Peroxisome proliferator-activated receptor (PPAR)? activation, through rosiglitazone treatment, reduced the rate of ?-GalCer-induced late PTB and improved neonatal survival. Administration of ?-GalCer in the third trimester suppressed PPAR? activation, as shown by the downregulation of Fabp4 and Fatp4 in myometrial and decidual tissues, respectively; this suppression was rescued by rosiglitazone treatment. Administration of ?-GalCer in the third trimester induced an increase in the activation of conventional CD4(+) T cells in myometrial tissues and the infiltration of activated macrophages, neutrophils, and mature dendritic cells to myometrial and/or decidual tissues. All of these effects were blunted after rosiglitazone treatment. Administration of ?-GalCer also upregulated the expression of inflammatory genes at the maternal-fetal interface and systemically, and rosiglitazone treatment partially attenuated these responses. Finally, an increased infiltration of activated iNKT-like cells in human decidual tissues is associated with noninfection-related preterm labor/birth. Collectively, these results demonstrate that iNKT cell activation in vivo leads to late PTB by initiating innate and adaptive immune responses and suggest that the PPAR? pathway has potential as a target for prevention of this syndrome.

Dataset Information

Acute invariant NKT cell activation triggers an immune response that drives prominent changes in iron homeostasis.

Publications

Acute invariant NKT cell activation triggers an immune response that drives prominent changes in iron homeostasis.

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