THE ROLE OF THE HEMOCHROMATOSIS PROTEIN HFE IN MACROPHAGE METABOLISM

Mutations in the iron-metabolic gene HFE are the most common cause for hereditary hemochromatosis (HH). The disease is characterized by insufficient production of the iron hormone hepcidin, leading to harmful, increased iron deposition in multiple tissues. Non-liver resident macrophages lacking Hfe show low intracellular iron independently of hepatic hepcidin expression1. Mice with a constitutive (Hfe-/-) or selective myeloid-Hfe deficiency (HfeLysMCre) show an improved survival during endotoxin shock and Salmonella infection1,2, linking Hfe in macrophages to inflammatory responses. Since iron content and metabolic reprogramming are hallmarks of macrophage phenotype and function, we postulate that Hfe acts in a macrophage specific manner and influences metabolism and mitochondrial function. 

To characterize the metabolic phenotype of macrophages lacking Hfe, we performed a real-time respirometry analysis (Seahorse, Agilent) on bone marrow derived macrophages from HfeLysMCre and Hfe-/- mice. Enzymatic activity and metabolite abundance measurements revealed further insights.

Hfe-deficient macrophages show impaired glycolysis and decreased respirational function. Activity of aconitase and succinate-dehydrogenase (SDHB) are compromised, leading to increased succinate levels. Macrophages lacking Hfe, show altered mitochondrial and metabolic capacities leading to a bioenergetic shift and along with the iron-poor phenotype, could explain the differential immune response and possibly revealing a macrophage-specific action of Hfe. 



1. Tangudu, N. K. et al. Macrophage-HFE controls iron metabolism and immune responses in aged mice. Haematologica (2021).



2. Nairz, M. et al. Cell-specific expression of Hfe determines the outcome of Salmonella enterica serovar Typhimurium infection in mice. Haematologica (2020)