BackgroundOver the last few years, accumulating data have implicated a role for ferritin as a signaling molecule and direct mediator of the immune system. Hyperferritinemia is associated with a multitude of clinical conditions and with worse prognosis in critically ill patients.DiscussionThere are four uncommon medical conditions characterized by high levels of ferritin, namely the macrophage activation syndrome (MAS), adult onset Still’s disease (AOSD), catastrophic antiphospholipid syndrome (cAPS) and septic shock, that share a similar clinical and laboratory features, and also respond to similar treatments, suggesting a common pathogenic mechanism. Ferritin is known to be a pro-inflammatory mediator inducing expression of pro-inflammatory molecules, yet it has opposing actions as a pro-inflammatory and as an immunosuppressant. We propose that the exceptionally high ferritin levels observed in these uncommon clinical conditions are not just the product of the inflammation but rather may contribute to the development of a cytokine storm.SummaryHere we review and compare four clinical conditions and the role of ferritin as an immunomodulator. We would like to propose including these four conditions under a common syndrome entity termed “Hyperferritinemic Syndrome”.

In mammalian cells, regulation of the expression of proteins involved in iron metabolism is achieved through interactions of iron-sensing proteins known as iron regulatory proteins (IRPs), with transcripts that contain RNA stem-loop structures referred to as iron responsive elements (IREs). Two distinct but highly homologous proteins, IRP1 and IRP2, bind IREs with high affinity when cells are depleted of iron, inhibiting translation of some transcripts, such as ferritin, or turnover of others, such as the transferrin receptor (TFRC). IRPs sense cytosolic iron levels and modify expression of proteins involved in iron uptake, export and sequestration according to the needs of individual cells. Here we generate mice with a targeted disruption of the gene encoding Irp2 (Ireb2). These mutant mice misregulate iron metabolism in the intestinal mucosa and the central nervous system. In adulthood, Ireb2(-/-) mice develop a movement disorder characterized by ataxia, bradykinesia and tremor. Significant accumulations of iron in white matter tracts and nuclei throughout the brain precede the onset of neurodegeneration and movement disorder symptoms by many months. Ferric iron accumulates in the cytosol of neurons and oligodendrocytes in distinctive regions of the brain. Abnormal accumulations of ferritin colocalize with iron accumulations in populations of neurons that degenerate, and iron-laden oligodendrocytes accumulate ubiquitin-positive inclusions. Thus, misregulation of iron metabolism leads to neurodegenerative disease in Ireb2(-/-) mice and may contribute to the pathogenesis of comparable human neurodegenerative diseases.

The two iron regulatory proteins IRP1 and IRP2 bind to transcripts of ferritin, transferrin receptor and other target genes to control the expression of iron metabolism proteins at the post-transcriptional level. Here we compare the effects of genetic ablation of IRP1 to IRP2 in mice. IRP1À/À mice misregulate iron metabolism only in the kidney and brown fat, two tissues in which the endogenous expression level of IRP1 greatly exceeds that of IRP2, whereas IRP2À/À mice misregulate the expression of target proteins in all tissues. Surprisingly, the RNA-binding activity of IRP1 does not increase in animals on a lowiron diet that is sufficient to activate IRP2. In animal tissues, most of the bifunctional IRP1 is in the form of cytosolic aconitase rather than an RNA-binding protein.Our findings indicate that the small RNA-binding fraction of IRP1, which is insensitive to cellular iron status, contributes to basal mammalian iron homeostasis, whereas IRP2 is sensitive to iron status and can compensate for the loss of IRP1 by increasing its binding activity. Thus, IRP2 dominates post-transcriptional regulation of iron metabolism in mammals.

The serum ferritin concentration is a clinical parameter measured widely for the differential diagnosis of anemia. Its levels increase with elevations of tissue iron stores and with inflammation, but studies on cellular sources of serum ferritin as well as its subunit composition, degree of iron loading and glycosylation have given rise to conflicting results. To gain further understanding of serum ferritin, we have used traditional and modern methodologies to characterize mouse serum ferritin. We find that both splenic macrophages and proximal tubule cells of the kidney are possible cellular sources for serum ferritin and that serum ferritin is secreted by cells rather than being the product of a cytosolic leak from damaged cells. Mouse serum ferritin is composed mostly of L-subunits, whereas it contains few H-subunits and iron content is low. L-subunits of serum ferritin are frequently truncated at the C-terminus, giving rise to a characteristic 17-kD band that has been previously observed in lysosomal ferritin. Taken together with the fact that mouse serum ferritin is not detectably glycosylated, we propose that mouse serum ferritin is secreted through the nonclassical lysosomal secretory pathway. (Blood. 2010;116(9):1574-1584) IntroductionFerritin in mammals is a mostly intracellular, cytosolic iron storage and detoxification protein. It consists of H-and L-subunits that assemble into a 24-subunit hollow sphere in which iron is sequestered. 1 However, ferritin can also be detected extracellularly, in cerebrospinal fluid and sinovial fluid. In serum it is an extracellular ferritin that has been used extensively in diagnostic tests. In the clinical setting, serum ferritin evaluation is most commonly used to estimate body iron stores as low serum ferritin correlates with iron depletion, whereas high serum ferritin correlates with elevated body iron stores or with inflammation in patients with normal body iron stores. 2,3 Characterization of serum ferritin has produced many controversial results regarding subunit composition, iron content and other features. It has been compared in some studies to the "natural apoferritin" fraction found in many tissues, which is essentially devoid of iron 4 while other studies have claimed that serum ferritin contains considerable amounts of iron. 5 In insects, ferritin is a secreted protein composed of 2 types of subunits and the heteropolymer functions most likely as an iron transporter in the hemolymph. Each of the subunits has a classical secretion signal and ferritin is secreted from the insect fat body. 6 In contrast, mammalian H-and L-ferritin subunits lack signals mediating endoplasmic reticulum (ER) targeting, but ferritin can traffic to the lysosomal compartment through autophagy. 7 Binding of human serum ferritin to the lectin Concanavalin A (ConA) has previously suggested that ferritin is glycosylated 8,9 and actively secreted through the ER-Golgi pathway. 10 Indeed, it was shown in hepatocyte cell-models that inhibition of ER-Golgi trafficking abolished secretion o...

Iron-regulatory proteins (IRPs) 1 and 2 posttranscriptionally regulate expression of transferrin receptor (TfR), ferritin, and other iron metabolism proteins. Mice with targeted deletion of IRP2 overexpress ferritin and express abnormally low TfR levels in multiple tissues. Despite this misregulation, there are no apparent pathologic consequences in tissues such as the liver and kidney. However, in the central nervous system, evidence of abnormal iron metabolism in IRP2 ؊/؊ mice precedes the development of adult-onset progressive neurodegeneration, characterized by widespread axonal degeneration and neuronal loss. Here, we report that ablation of IRP2 results in ironlimited erythropoiesis. TfR expression in erythroid precursors of IRP2 ؊/؊ mice is reduced, and bone marrow iron stores are absent, even though transferrin saturation levels are normal. Marked overexpression of 5-aminolevulinic acid synthase 2 (Alas2) results from loss of IRPdependent translational repression, and markedly increased levels of free protoporphyrin IX and zinc protoporphyrin are generated in IRP2 ؊/؊ erythroid cells. IRP2 IntroductionIron functions as an indispensable cofactor for numerous enzymes and proteins in mammals, and regulation of iron uptake and distribution within animals is accordingly highly regulated. 1,2 Intestinal iron absorption and tissue iron storage are optimized to deliver the iron needed for numerous metabolic processes, including heme synthesis. The recently identified peptide hormone, hepcidin, is responsible for appropriately coordinating intestinal iron uptake and macrophage iron release to meet the needs of the organism and to maintain normal serum transferrin saturation levels. 3 In most tissues, the circulating pool of diferric transferrin serves as the major source of iron for individual cells. When diferric transferrin (Tf) binds to transferrin receptors (TfRs), the Tf-TfR complex internalizes in endosomes, where acidification facilitates release of free iron, 4 and the membrane iron transporter divalent metal transporter 1 (DMT1) (SLC11A2) transports iron into the cytosol. 5,6 In the cytosol, iron is incorporated into iron proteins or transported to cellular organelles, and excess cytosolic iron is sequestered and stored by ferritin. 6,7 Cells regulate expression of ferritin and TfR to optimize cytosolic iron levels. When cells are iron depleted, they increase TfR expression and uptake of transferrinbound iron, while they simultaneously decrease expression of ferritin and iron sequestration. Proteins known as iron regulatory proteins (IRPs) coordinately regulate expression of TfR, ferritin, and numerous other iron metabolism proteins. IRP1 and IRP2 are homologous genes that monitor cytosolic iron levels. When cells are iron depleted, IRPs bind to RNA motifs known as iron-responsive elements (IREs) within transcripts that encode iron metabolism proteins (reviewed in Rouault and Klausner 1 ; and Hentze et al 2 ). IREs are found in numerous transcripts, including ferritin H-and L-chains, TfR1, 7 erythrocyti...