Abstract
Control of systemic iron homeostasis is interconnected with the inflammatory response through the key iron regulator, the antimicrobial peptide hepcidin. We have previously shown that mice with iron deficiency anemia (IDA)-low hepcidin show a pro-inflammatory response that is blunted in iron deficient-high hepcidin Tmprss6 KO mice. The transcriptional response associated with chronic hepcidin overexpression due to genetic inactivation of Tmprss6 is unknown. By using whole genome transcription profiling of the liver and analysis of spleen immune-related genes we identified several functional pathways differentially expressed in Tmprss6 KO mice, compared to IDA animals and thus irrespective of the iron status. In the effort of defining genes potentially targets of Tmprss6 we analyzed liver gene expression changes according to the genotype and independently of treatment. Tmprss6 inactivation causes down-regulation of liver pathways connected to immune and inflammatory response as well as spleen genes related to macrophage activation and inflammatory cytokines production. The anti-inflammatory status of Tmprss6 KO animals was confirmed by the down-regulation of pathways related to immunity, stress response and intracellular signaling in both liver and spleen after LPS treatment. Opposite to Tmprss6 KO mice, Hfe−/− mice are characterized by iron overload with inappropriately low hepcidin levels. Liver expression profiling of Hfe−/− deficient versus iron loaded mice show the opposite expression of some of the genes modulated by the loss of Tmprss6. Altogether our results confirm the anti-inflammatory status of Tmprss6 KO mice and identify new potential target pathways/genes of Tmprss6.
Highlights
Epidemiological studies suggest that iron modulates the susceptibility to infections/inflammation, but the molecular mechanisms underlying this phenomenon are incompletely understood
Hepcidin expression in inflammation is activated by IL6 and IL22 [3] through phosphorylated Stat3 (PStat3) binding to the hepcidin promoter, in a region closed to the Bone Morphogenetic Protein (BMP) Responsive Elements (BRE) binding sites [4]
Tmprss6 KO mice show a more severe iron deficiency anemia than control mice (Hb 97+/21.5 vs 126+/24.4 g/L [11]), liver iron content is comparable in the two groups (106.8+/ 214.4 in Tmprss6 KO mice vs 101.8+/211.6 mg iron/g liver in IDA animals) and does not significantly change after LPS treatment, as already reported for iron deficient animals [11]
Summary
Epidemiological studies suggest that iron modulates the susceptibility to infections/inflammation, but the molecular mechanisms underlying this phenomenon are incompletely understood. Hepcidin expression in inflammation is activated by IL6 and IL22 [3] through phosphorylated Stat (PStat3) binding to the hepcidin promoter, in a region closed to the Bone Morphogenetic Protein (BMP) Responsive Elements (BRE) binding sites [4]. Hepcidin binds the sole cellular iron exporter ferroportin triggering its internalization and degradation, reducing iron flux from duodenal enterocytes and macrophages and resulting in hypoferremia, a protective response against microbial growth [5]. Hepcidin-ferroportin interaction in macrophages has been reported to cause JAK2-related transcriptional changes that negatively modulate the cytokine-induced inflammatory response [6], recently the phosphorylation of JAK2 as a result of hepcidin-ferroportin interaction has been disputed [7]
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