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Iron Metabolism & its Disorders
Cell-specific expression of Hfe determines the outcome of Salmonella enterica serovar Typhimurium infection in mice
Manfred Nairz,1* Christoph Metzendorf,2,3* Maja Vujic-Spasic,2,3,4+ Anna-Maria Mitterstiller,1+ Andrea Schroll,1 David Haschka,1 Alexander Hoffmann,1,5 Laura von Raffay,1 Richard Sparla,2,3 Christian W. Huck,6 Heribert Talasz,7 Patrizia L. Moser,8
Martina U. Muckenthaler2,3# and Günter Weiss1,5#
1Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria; 2Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, INF 350, Heidelberg, Germany; 3Molecular Medicine Partnership Unit, Heidelberg, Germany; 4Institute of Comparative Molecular Endocrinology, Ulm University, Ulm, Germany; 5Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria; 6Institute for Analytical Chemistry and Radiochemistry, University of Innsbruck, Innsbruck, Austria; 7Biocenter, Division of Clinical Biochemistry, Medical University of Innsbruck, Innsbruck, Austria
and 8Institute of Pathology, INNPATH, Innsbruck, Austria
*MN and CM contributed equally as co-first authors
+MV-S and A-MM contributed equally as co-second authors #MM and GW contributed equally as co-senior authors
ABSTRACT
Mutations in HFE cause hereditary hemochromatosis type I hall- marked by increased iron absorption, iron accumulation in hepa- tocytes and iron deficiency in myeloid cells. HFE encodes an MHC-I like molecule, but its function in immune responses to infection remains incompletely understood. Here, we investigated putative roles of Hfe in myeloid cells and hepatocytes, separately, upon infection with Salmonella Typhimurium, an intracellular bacterium with iron-dependent vir- ulence. We found that constitutive and macrophage-specific deletion of Hfe protected infected mice. The propagation of Salmonella in macrophages was reduced due to limited intramacrophage iron availability for bacterial growth and increased expression of the anti-microbial enzyme nitric oxide synthase-2. By contrast, mice with hepatocyte-specific deletion of Hfe suc- cumbed earlier to Salmonella infection because of unrestricted extracellular bacterial replication associated with high iron availability in the serum and impaired expression of essential host defense molecules such as inter- leukin-6, interferon-g and nitric oxide synthase-2. Wild-type mice subject- ed to dietary iron overload phenocopied hepatocyte-specific Hfe deficiency suggesting that increased iron availability in the serum is deleterious in Salmonella infection and underlies impaired host immune responses. Moreover, the macrophage-specific effect is dominant over hepatocyte- specific Hfe-depletion, as Hfe knockout mice have increased survival despite the higher parenchymal iron load associated with systemic loss of Hfe. We conclude that cell-specific expression of Hfe in hepatocytes and macrophages differentially affects the course of infections with specific pathogens by determining bacterial iron access and the efficacy of anti- microbial immune effector pathways. This may explain the high frequen- cy and evolutionary conservation of human HFE mutations.
Introduction
Most patients with hereditary hemochromatosis (HH) show homozygous C282Y missense mutations in the gene HFE.1,2 They are hallmarked by parenchy- mal iron deposition particularly in hepatocytes, cardiomyocytes and pancreatic
Ferrata Storti Foundation
Haematologica 2021 Volume 106(12):3149-3161
Correspondence:
MARTINA U. MUCKENTHALER
martina.muckenthaler@med.uni-heidelberg.de
GÜNTER WEISS
guenter.weiss@i-med.ac.at
Received: December 3, 2019. Accepted: September 30, 2020. Pre-published: October 13, 2020.
https://doi.org/10.3324/haematol.2019.241745 ©2021 Ferrata Storti Foundation
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