'Ride on the ferrous wheel'--the cycle of iron in macrophages in health and disease.

Iron homeostasis and macrophage biology are closely interconnected. On the one hand, iron exerts multiple effects on macrophage polarization and functionality. On the other hand, macrophages are central for mammalian iron homeostasis. The phagocytosis of senescent erythrocytes and their degradation by macrophages enable efficient recycling of iron and the maintenance of systemic iron balance. Macrophages express multiple molecules and proteins for the acquisition and utilization of iron and many of these pathways are affected by inflammatory signals. Of note, iron availability within macrophages has significant effects on immune effector functions and metabolic pathways within these cells. This review summarizes the physiological and pathophysiological aspects of macrophage iron metabolism and highlights its relevant consequences on immune function and in common diseases such as infection and atherosclerosis.

Ferroportin diseases: functional studies, a link between genetic and clinical phenotype.

Ferroportin (FPN) mediates iron export from cells and this function is modulated by serum hepcidin. Mutations in the FPN gene (SLC40A1) lead to autosomal dominant iron overload diseases related either to loss or to gain of function, and usually characterized by normal or low transferrin saturation versus elevated transferrin saturation, respectively. However, for the same mutation, the phenotypic expression may vary from one patient to another. Using in vitro overexpression of wild-type or mutant FPN proteins, we characterized the functional impact of five recently identified FPN gene mutations regarding FPN localization, cell iron status, and hepcidin sensitivity. Our aim was to integrate functional results and biological findings in probands and relatives. We show that while the p.Arg371Gln (R371Q) mutation had no impact on studied parameters, the p.Trp158Leu (W158L), p.Arg88Gly (R88G), and p.Asn185Asp (N185D) mutations caused an iron export defect and were classified as loss-of-function mutations. The p.Gly204Ser (G204S) mutation induced a gain of FPN function. Functional studies are useful to determine whether or not a FPN gene mutation found in an iron overloaded patient is deleterious and to characterize its biological impact, especially when family studies are not fully informative and/or additional confounding factors may affect bio-clinical expression.

Screening of BCS1L mutations in severe neonatal disorders suspicious for mitochondrial cause.

The BCS1L gene encodes a chaperone responsible for assembly of respiratory chain complex III (CIII). A homozygous point mutation (232A-->G) has been found as the genetic etiology for fetal growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death (GRACILE) syndrome (MIM 603358). Variable phenotypes have been found with other mutations. Our aim was to assess whether 232A-->G or other BCS1L mutations were present in infants (n = 21) of Finnish origin with severe, lethal disease compatible with mitochondrial disorder. A further aim was to confirm the GRACILE genotype-phenotype constancy (n = 8). Three new cases with homozygous 232A-->G mutation were identified; all had the primary GRACILE characteristics. No other mutations were found in the gene in other cases. All infants with GRACILE syndrome had the typical mutation. In conclusion, the rather homogenous population of Finns seems to have a specific BCS1L mutation that, as homozygous state, causes GRACILE syndrome, whereas other mutations are rare or not occurring. Thus, the novel clinical implication of this study is to screen for BCS1L mutations only if CIII is dysfunctioning or lacking Rieske protein, and to assess 232A-->G mutation in cases with GRACILE syndrome.

Vibrio vulnificus necrotizing fasciitis of the calf presenting with compartment syndrome.

We describe a 17-year-old boy with congenital spherocytosis and iron overload who presented with compartment syndrome of the calf as the initial manifestation of Vibrio vulnificus infection after minor trauma in a contaminated fish pond. The disease was complicated by necrotizing fasciitis requiring above the knee amputation. Childhood diseases associated with iron overload pose an increased risk for complicated V. vulnificus infections.

Exogenous apotransferrin and exchange transfusions in hereditary iron overload disease.

OBJECTIVE: To investigate whether apotransferrin administration and exchange transfusion can improve outcome in patients with the recently described recessive congenital iron overload disease, presenting with intrauterine growth retardation, severe lactic acidosis, aminoaciduria, and hemosiderosis of the liver that so far has been treatment-resistant and lethal. METHODOLOGY: Because the patients have hypotransferrinemia, hyperferritinemia, increased transferrin saturation, and bleomycin detectable iron in plasma, we designed a treatment regime aiming at decreasing free iron and iron overload. The serum transferrrin concentration was increased to adult level (2-5 g/L) by intravenous apotransferrin administrations and thereafter exchange transfusion was performed. RESULTS: Two patients were treated. In patient 1, the transferrin saturation decreased from a baseline value of 100% and remained normal after the third exchange transfusion, and in patient 2, a reversible beneficial effect was seen on transferrin saturation and bleomycin-detectable iron. However, both infants died later of the disease, at 10 and 8 weeks of age, respectively. CONCLUSIONS: Exogenous apotransferrin administration proved to be safe and might deserve evaluation in other neonatal diseases with presence of free iron in plasma.