A strong anti-inflammatory signature revealed by liver transcription profiling of Tmprss6-/- mice.
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.
Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
Michela
M
Riba
Marco
M
Rausa
Melissa
M
Sorosina
Davide
D
Cittaro
Jose Manuel
JM
Garcia Manteiga
Antonella
A
Nai
Alessia
A
Pagani
Filippo
F
Martinelli-Boneschi
Elia
E
Stupka
Clara
C
Camaschella
Laura
L
Silvestri
D000818:Animals; D015153:Blotting, Western; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012697:Serine Endopeptidases; C467801:matriptase 2