A novel inflammatory pathway mediating rapid hepcidin-independent hypoferremia

Abstract

Key Points• Stimulation of Toll-like receptors 2 and 6 reduces ferroportin expression in mouse macrophages by hepcidin-independent mechanism(s).• Reduced expression of ferroportin in macrophages that recycle iron from red cells is sufficient to rapidly induce hypoferremia in mice.Regulation of iron metabolism and innate immunity are tightly interlinked. The acute phase response to infection and inflammation induces alterations in iron homeostasis that reduce iron supplies to pathogens. The iron hormone hepcidin is activated by such stimuli causing degradation of the iron exporter ferroportin and reduced iron release from macrophages, suggesting that hepcidin is the crucial effector of inflammatory hypoferremia. Here, we report the discovery of an acute inflammatory condition that is mediated by Toll-like receptors 2 and 6 (TLR2 and TLR6) and which induces hypoferremia in mice injected with TLR ligands. Stimulation of TLR2/TLR6 triggers profound decreases in ferroportin messenger RNA and protein expression in bone marrow-derived macrophages, liver, and spleen of mice without changing hepcidin expression. Furthermore, C326S ferroportin mutant mice with a disrupted hepcidin/ferroportin regulatory circuitry respond to injection of the TLR2/6 ligands FSL1 or PAM3CSK4 by ferroportin downregulation and a reduction of serum iron levels. Our findings challenge the prevailing role of hepcidin in hypoferremia and suggest that rapid hepcidin-independent ferroportin downregulation in the major sites of iron recycling may represent a first-line response to restrict iron access for numerous pathogens. (Blood. 2015;125(14): [2265][2266][2267][2268][2269][2270][2271][2272][2273][2274][2275] IntroductionIron plays a central role in host-pathogen interactions.1 Most pathogens require iron for proliferation and full virulence. The innate immune system fights infections by sequestration of iron in macrophages of the reticuloendothelial system. The resulting hypoferremia represents a major host defense strategy and promotes anemia of inflammation, a form of anemia commonly associated with infectious and inflammatory conditions as well as cancer. Toll-like receptors (TLRs) are key sensors of the innate immune system.3 They recognize pathogen-associated molecular patterns (PAMPs) and control the hypoferremic host response. Lipopolysaccharide (LPS) is a cell wall component of gram-negative bacteria recognized by TLR4. LPS injection into mice causes the release of proinflammatory cytokines and triggers a wellcharacterized acute phase response including induction of the hepatic iron hormone hepcidin 4-6 by interleukin-6 (IL-6). 7,8 Hepcidin binds to and causes internalization and degradation of the iron exporter ferroportin, which limits iron release from iron-exporting cells such as macrophages, hepatocytes, and duodenal enterocytes. Diminished iron export from macrophages that recycle iron from senescent red cells rapidly induces hypoferremia due to the high iron demand of erythropoiesis. 10,11 Excess levels of hepcidin have been recog...

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

“…Previous studies with infection models have shown hepcidin induction occurring during the first 12 h of infection (64), and the moderate change we observe is after the time window at which the hepcidin transcripts increase. The notable decrease in FPN mRNA suggests that hepatic iron regulation at this time point may also involve additional hepcidin-independent pathways that involve transcriptional regulation of FPN (65,66). The mRNA levels of TfR appear unchanged while DMT1 mRNA levels are reduced in the infected mice compared with the mockinfected mice.…”

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

“…In light of this, we examined expression patterns of other genes involved in iron utilization or in the inflammation pathway (reviewed by Ganz, 2011;Ginzburg and Rivella, 2011;Guida et al, 2015;Kim and Nemeth, 2015;Li et al, 2014;Nagata, 2007;Rivella, 2015;Yoshida et al, 2005b) to address indirect or Nan-KLF1-independent causes for the inefficient erythropoiesis (Gillinder et al, 2016). Expression is either unchanged [hemochromatosis (Hfe), IRP1 (Aco1), aconitase (Aco2), Flvcr1 (Mfsd7b); Fig.…”

Investigation of manganese homeostasis in dogs with anaemia and chronic enteropathy

“…As a further variable, Vitamin D is an important suppressor of hepcidin, and dogs with severe CE have been shown to have reduced vitamin D concentrations (Gow et al, 2011;Bacchetta et al, 2014). Moreover, in inflammatory conditions, the action of metal transporters can be disrupted, independently of hepcidin (Guida et al, 2015). In human IBD, active disease was seen to correlate with decreased mucosal DMT1 expression (Wu et al, 2015).…”