Nifedipine Affects the Course of Salmonella enterica Serovar Typhimurium Infection by Modulating Macrophage Iron Homeostasis
Open accessAbstract
BACKGROUND: Iron overload can adversely influence the course of infection by increasing microbial replication and suppressing antimicrobial immune effector pathways. Recently, we have shown that the calcium channel blocker nifedipine can mobilize tissue iron in mouse models of iron overload. We therefore investigated whether nifedipine treatment affects the course of infection with intracellular bacteria via modulation of iron homeostasis. METHODS: The effect of nifedipine on intramacrophage replication of bacteria and modulation of cellular iron homeostasis was investigated in the murine macrophage cell line RAW264.7, and the impact of nifedipine treatment on the course of systemic infection was investigated in C57BL/6 mice in vivo. RESULTS: In RAW264.7 cells, nifedipine treatment significantly reduced intracellular bacterial survival of Salmonella enterica serovar Typhimurium and Chlamydophila pneumoniae. This could be attributed to the induction of the iron exporter ferroportin 1, which limited the availability of iron for intracellular Salmonella. When C57BL/6 mice were infected intraperitoneally with Salmonella and subsequently injected with nifedipine for 3 consecutive days, bacterial counts in livers and spleens were significantly reduced and survival of the mice significantly was prolonged compared with solvent-treated littermates. Nifedipine treatment increased expression of ferroportin 1 in the spleen, whereas splenic levels of the iron storage protein ferritin and serum iron concentrations were reduced. CONCLUSIONS: Our data provide evidence for a novel mechanism whereby nifedipine enhances host resistance to intracellular pathogens via limitation of iron availability.
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Control over iron homeostasis appears decisive for the course of M. tuberculosis infection.
“In conclusion, control over iron homeostasis appears to be decisive for the course of M. tuberculosis infection and attempt to modulate macrophage iron status or bacterial iron acquisition may be attractive strategies for novel treatment approach of this devastating infection in an era of rapidly emerging drug resistance (231, 232).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [232]
These data support the general idea that modulation of macrophage iron homeostasis is a promising way to control their immune functions and alter myeloid-driven disease processes in infection, auto-immunity, atherosclerosis, and possibly cancer.
“These novel and exciting data support the general idea that the modulation of macrophage iron homeostasis is a promising way to control their immune functions and alter myeloid-driven disease processes in infection, auto-immunity, atherosclerosis, and possibly also cancer [143, 167]”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [143]
Nifedipine, a calcium channel blocker that promotes Fe efflux from Mø, enhances host resistance to Salmonella infection in mice.
“This was demonstrated, as a proof of principle, using Nifedipine, a calcium channel blocker that promotes Fe efflux from Mø and enhances host resistance to Salmonella infection in mice [233].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [233]
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- Authors
- Mair, S. M., Nairz, M., Bellmann-Weiler, R., Muehlbacher, T., Schroll, A., Theurl, I., Moser, P. L., Talasz, H., Fang, F. C., & Weiss, G.
- Affiliations
- Innsbruck Medical University (AT)
- University of Washington (US)
- Venue
- The Journal of Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-09-01
- Volume
- 204
- Issue
- 5
- Pages
- 685-694
- ISSN
- 0022-1899 (ISSN-L)
- 1537-6613
- PMC
- PMC3156106
- OpenAlex
- W2002442448
- Cited by
- 33
- References
- 51
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 4 · 2022: 1 · 2021: 4 · 2020: 3 · 2018: 3 · 2017: 1 · 2016: 2 · 2015: 3 · 2014: 5 · 2013: 2 · 2012: 2
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Infectious Diseases (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI77629, R01AI077629, AI 39557)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Agricultural and Biological Sciences › Food Science › Salmonella and Campylobacter epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- nifedipine, Salmonella typhimurium, iron homeostasis, ferroportin 1, iron export, iron overload, macrophages, intracellular bacterial replication, Chlamydia pneumoniae, calcium channel blockers, ferritin, serum iron
- MeSH terms
- Ferroportin, Animals, Calcium Channel Blockers, Cell Line, Ferritins, Iron, Liver, Macrophages, Male, Mice, Inbred C57BL, Nifedipine, RNA, Messenger, Salmonella Infections, Animal, Salmonella typhimurium, Spleen, Cytokines, Chlamydophila pneumoniae, Chlamydophila Infections, Cation Transport Proteins, Mice, Bacterial Load
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