Abstract
BackgroundInflammatory stimuli induce the hepatic iron regulatory hormone hepcidin, which contributes to anaemia of inflammation (AI). Hepcidin expression is regulated by the bone morphogenetic protein (BMP) and the interleukin-6 (IL-6) signalling pathways. Prior results indicate that the BMP type I receptor ALK3 is mainly involved in the acute inflammatory hepcidin induction four and 72 h after IL-6 administration. In this study, the role of ALK3 in a chronic model of inflammation was investigated. The intact, heat-killed bacterium Brucella abortus (BA) was used to analyse its effect on the development of inflammation and hypoferremia in mice with hepatocyte-specific Alk3-deficiency (Alk3fl/fl; Alb-Cre) compared to control (Alk3fl/fl) mice.ResultsAn iron restricted diet prevented development of the iron overload phenotype in mice with hepatocyte-specific Alk3 deficiency. Regular diet leads to iron overload and increased haemoglobin levels in these mice, which protects from the development of AI per se. Fourteen days after BA injection Alk3fl/fl; Alb-Cre mice presented milder anaemia (Hb 16.7 g/dl to 11.6 g/dl) compared to Alk3fl/fl control mice (Hb 14.9 g/dl to 8.6 g/dl). BA injection led to an intact inflammatory response in all groups of mice. In Alk3fl/fl; Alb-Cre mice, SMAD1/5/8 phosphorylation was reduced after BA as well as after infection with Staphylococcus aureus. The reduction of the SMAD1/5/8 signalling pathway due to hepatocyte-specific Alk3 deficiency partly suppressed the induction of STAT3 signalling.ConclusionThe results reveal in vivo, that 1) hepatocyte-specific Alk3 deficiency partly protects from AI, 2) the development of hypoferremia is partly dependent on ALK3, and 3) the ALK3/BMP/hepcidin axis may serve as a possible therapeutic target to attenuate AI.
Highlights
Inflammatory stimuli induce the hepatic iron regulatory hormone hepcidin, which contributes to anaemia of inflammation (AI)
The results indicate that development of the iron overload phenotype in Alk3fl/fl; Alb-Cyclization recombination (Cre) compared to Alk3fl/fl mice was prevented by the iron-deficient diet
Fourteen days after Brucella abortus (BA) administration SMAD1/5/8 phosphorylation seems reduced in control mice and still absent in Activin receptor-like kinase (Alk3) deficient mice (Fig. 8c-d). These results indicate that bone morphogenetic protein (BMP) signalling is abrogated in mice with hepatocyte-specific Alk3 deficiency, so that ALK3 is the critical receptor for intact BMP/Small Mothers Against Decapentaplegic homolog (SMAD) signalling and that SMAD activation is required for the STAT3 pathway
Summary
Inflammatory stimuli induce the hepatic iron regulatory hormone hepcidin, which contributes to anaemia of inflammation (AI). In mice with hepatocyte-specific Alk deficiency STAT3 was phosphorylated by IL-6, but the hepcidin induction was impeded and hepcidin levels remained at about 1–5% compared to control mice in short term experiments [13, 14] The susceptibility of these mice to develop AI had yet to be investigated. The intraperitoneal application of a single dose of heat-killed Brucella abortus (BA) particles was utilized in this study to induce chronic inflammation and the development of AI in mice This well described murine model of AI features the following hallmarks of the disease: i) early hepcidin induction, ii) cytokine release and, iii) impaired erythropoiesis [15,16,17]
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