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Iron, inflammation, and early death in adults with sickle cell disease.

Circulation research (2014-11-08)
Eduard J van Beers, Yanqin Yang, Nalini Raghavachari, Xin Tian, Darlene T Allen, James S Nichols, Laurel Mendelsohn, Sergei Nekhai, Victor R Gordeuk, James G Taylor, Gregory J Kato
ABSTRACT

Patients with sickle cell disease (SCD) have markers of chronic inflammation, but the mechanism of inflammation and its relevance to patient survival are unknown. To assess the relationship between iron, inflammation, and early death in SCD. Using peripheral blood mononuclear cell transcriptome profile hierarchical clustering, we classified 24 patients and 10 controls in clusters with significantly different expression of genes known to be regulated by iron. Subsequent gene set enrichment analysis showed that many genes associated with the high iron cluster were involved in the toll-like receptor system (TLR4, TLR7, and TLR8) and inflammasome complex pathway (NLRP3, NLRC4, and CASP1). Quantitative PCR confirmed this classification and showed that ferritin light chain, TLR4, and interleukin-6 expression were >100-fold higher in patients than in controls (P<0.001). Further linking intracellular iron and inflammation, 14 SCD patients with a ferroportin Q248H variant that causes intracellular iron accumulation had significantly higher levels of interleukin-6 and C-reactive protein compared with 14 matched SCD patients with the wild-type allele (P<0.05). Finally, in a cohort of 412 patients followed for a median period of 47 months (interquartile range, 24-82), C-reactive protein was strongly and independently associated with early death (hazard ratio, 3.0; 95% confidence interval, 1.7-5.2; P<0.001). Gene expression markers of high intracellular iron in patients with SCD are associated with markers of inflammation and mortality. The results support a model in which intracellular iron promotes inflammatory pathways, such as the TLR system and the inflammasome, identifying important new pathways for additional investigation.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Carbonyl iron, ≥97% Fe basis
Sigma-Aldrich
Iron, foil, thickness 0.25 mm, ≥99.99% trace metals basis
Sigma-Aldrich
Iron, granular, 10-40 mesh, >99.99% trace metals basis
Sigma-Aldrich
Iron, powder, <10 μm, ≥99.9% trace metals basis
Sigma-Aldrich
Iron, wire, diam. 1.0 mm, ≥99.9% trace metals basis
Sigma-Aldrich
Iron, ≥99%, reduced, powder (fine)
Sigma-Aldrich
Iron, wire, diam. 1.0 mm, ≥99.99% trace metals basis
Iron, foil, light tested, 25x25mm, thickness 0.01mm, 99.99+%
Iron, foil, 6mm disks, thickness 0.009mm, 99.85%
Iron, foil, 8mm disks, thickness 0.025mm, as rolled, 99.99+%
Iron, foil, 50mm disks, thickness 0.125mm, hard, 99.5%
Iron, foil, light tested, 25x25mm, thickness 0.025mm, as rolled, 99.99+%
Iron, foil, 5m coil, thickness 0.038mm, hard, 99.5%
Iron, foil, not light tested, 100x100mm, thickness 0.015mm, 99.85%
Iron, foil, 8mm disks, thickness 0.005mm, 99.85%
Iron, foil, 8mm disks, thickness 1.0mm, as rolled, 99.5%
Iron, foil, 6mm disks, thickness 0.003mm, 99.85%
Iron, foil, light tested, 50x50mm, thickness 0.075mm, hard, 99.5%
Iron, foil, 8mm disks, thickness 0.0125mm, 99.85%
Iron, foil, 8mm disks, thickness 0.125mm, as rolled, 99.99+%
Iron, foil, 5m coil, thickness 0.025mm, hard, 99.5%
Iron, foil, 6mm disks, thickness 0.015mm, 99.85%
Iron, foil, not light tested, 100x100mm, thickness 0.0125mm, 99.99+%
Iron, foil, light tested, 150x150mm, thickness 0.05mm, hard, 99.5%
Iron, foil, 8mm disks, thickness 0.9mm, as rolled, 99.5%
Iron, foil, light tested, 25x25mm, thickness 0.01mm, 99.85%
Iron, foil, light tested, 50x50mm, thickness 0.075mm, as rolled, 99.99+%
Iron, foil, 6mm disks, thickness 0.075mm, as rolled, 99.99+%
Iron, foil, 6mm disks, thickness 0.006mm, 99.85%
Iron, foil, not light tested, 100x100mm, thickness 0.004mm, 99.85%