Pharmacological Targeting of BMP6-SMAD Mediated Hepcidin Expression Does Not Improve the Outcome of Systemic Infections With Intra-Or Extracellular Gram-Negative Bacteria in Mice
IntroductionHepcidin is the systemic master regulator of iron metabolism as it degrades the cellular iron exporter ferroportin. In bacterial infections, hepcidin is upregulated to limit circulating iron for pathogens, thereby increasing iron retention in macrophages. This mechanism withholds iron fr...
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2021.705087/full |
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| author | Alexander Hoffmann Alexander Hoffmann Lara Valente de Souza Lara Valente de Souza Markus Seifert Markus Seifert Laura von Raffay Laura von Raffay David Haschka Philipp Grubwieser Manuel Grander Anna-Maria Mitterstiller Manfred Nairz Maura Poli Günter Weiss Günter Weiss |
| author_facet | Alexander Hoffmann Alexander Hoffmann Lara Valente de Souza Lara Valente de Souza Markus Seifert Markus Seifert Laura von Raffay Laura von Raffay David Haschka Philipp Grubwieser Manuel Grander Anna-Maria Mitterstiller Manfred Nairz Maura Poli Günter Weiss Günter Weiss |
| author_sort | Alexander Hoffmann |
| collection | DOAJ |
| description | IntroductionHepcidin is the systemic master regulator of iron metabolism as it degrades the cellular iron exporter ferroportin. In bacterial infections, hepcidin is upregulated to limit circulating iron for pathogens, thereby increasing iron retention in macrophages. This mechanism withholds iron from extracellular bacteria but could be of disadvantage in infections with intracellular bacteria. We aimed to understand the role of hepcidin in infections with intra- or extracellular bacteria using different hepcidin inhibitors.MethodsFor the experiments LDN-193189 and oversulfated heparins were used, which interact with the BMP6-SMAD pathway thereby inhibiting hepcidin expression. We infected male C57BL/6N mice with either the intracellular bacterium Salmonella Typhimurium or the extracellular bacterium Escherichia coli and treated these mice with the different hepcidin inhibitors.ResultsBoth inhibitors effectively reduced hepcidin levels in vitro under steady state conditions and upon stimulation with the inflammatory signals interleukin-6 or lipopolysaccharide. The inhibitors also reduced hepcidin levels and increased circulating iron concentration in uninfected mice. However, both compounds failed to decrease liver- and circulating hepcidin levels in infected mice and did not affect ferroportin expression in the spleen or impact on serum iron levels. Accordingly, both BMP-SMAD signaling inhibitors did not influence bacterial numbers in different organs in the course of E.coli or S.Tm sepsis.ConclusionThese data indicate that targeting the BMP receptor or the BMP-SMAD pathway is not sufficient to suppress hepcidin expression in the course of infection with both intra- or extracellular bacteria. This suggests that upon pharmacological inhibition of the central SMAD-BMP pathways during infection, other signaling cascades are compensatorily induced to ensure sufficient hepcidin formation and iron restriction to circulating microbes. |
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| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-12-21T17:26:09Z |
| publishDate | 2021-07-01 |
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| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-c302519a49e24bd787cddd5f6bdb80902022-12-21T18:56:02ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882021-07-011110.3389/fcimb.2021.705087705087Pharmacological Targeting of BMP6-SMAD Mediated Hepcidin Expression Does Not Improve the Outcome of Systemic Infections With Intra-Or Extracellular Gram-Negative Bacteria in MiceAlexander Hoffmann0Alexander Hoffmann1Lara Valente de Souza2Lara Valente de Souza3Markus Seifert4Markus Seifert5Laura von Raffay6Laura von Raffay7David Haschka8Philipp Grubwieser9Manuel Grander10Anna-Maria Mitterstiller11Manfred Nairz12Maura Poli13Günter Weiss14Günter Weiss15Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, AustriaChristian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, AustriaChristian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, AustriaChristian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, AustriaChristian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, AustriaDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, AustriaChristian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, AustriaIntroductionHepcidin is the systemic master regulator of iron metabolism as it degrades the cellular iron exporter ferroportin. In bacterial infections, hepcidin is upregulated to limit circulating iron for pathogens, thereby increasing iron retention in macrophages. This mechanism withholds iron from extracellular bacteria but could be of disadvantage in infections with intracellular bacteria. We aimed to understand the role of hepcidin in infections with intra- or extracellular bacteria using different hepcidin inhibitors.MethodsFor the experiments LDN-193189 and oversulfated heparins were used, which interact with the BMP6-SMAD pathway thereby inhibiting hepcidin expression. We infected male C57BL/6N mice with either the intracellular bacterium Salmonella Typhimurium or the extracellular bacterium Escherichia coli and treated these mice with the different hepcidin inhibitors.ResultsBoth inhibitors effectively reduced hepcidin levels in vitro under steady state conditions and upon stimulation with the inflammatory signals interleukin-6 or lipopolysaccharide. The inhibitors also reduced hepcidin levels and increased circulating iron concentration in uninfected mice. However, both compounds failed to decrease liver- and circulating hepcidin levels in infected mice and did not affect ferroportin expression in the spleen or impact on serum iron levels. Accordingly, both BMP-SMAD signaling inhibitors did not influence bacterial numbers in different organs in the course of E.coli or S.Tm sepsis.ConclusionThese data indicate that targeting the BMP receptor or the BMP-SMAD pathway is not sufficient to suppress hepcidin expression in the course of infection with both intra- or extracellular bacteria. This suggests that upon pharmacological inhibition of the central SMAD-BMP pathways during infection, other signaling cascades are compensatorily induced to ensure sufficient hepcidin formation and iron restriction to circulating microbes.https://www.frontiersin.org/articles/10.3389/fcimb.2021.705087/fullhepcidin inhibitorinfectionGram-negative bacteriaover-sulfated heparinsLDN-193189Salmonella |
| spellingShingle | Alexander Hoffmann Alexander Hoffmann Lara Valente de Souza Lara Valente de Souza Markus Seifert Markus Seifert Laura von Raffay Laura von Raffay David Haschka Philipp Grubwieser Manuel Grander Anna-Maria Mitterstiller Manfred Nairz Maura Poli Günter Weiss Günter Weiss Pharmacological Targeting of BMP6-SMAD Mediated Hepcidin Expression Does Not Improve the Outcome of Systemic Infections With Intra-Or Extracellular Gram-Negative Bacteria in Mice Frontiers in Cellular and Infection Microbiology hepcidin inhibitor infection Gram-negative bacteria over-sulfated heparins LDN-193189 Salmonella |
| title | Pharmacological Targeting of BMP6-SMAD Mediated Hepcidin Expression Does Not Improve the Outcome of Systemic Infections With Intra-Or Extracellular Gram-Negative Bacteria in Mice |
| title_full | Pharmacological Targeting of BMP6-SMAD Mediated Hepcidin Expression Does Not Improve the Outcome of Systemic Infections With Intra-Or Extracellular Gram-Negative Bacteria in Mice |
| title_fullStr | Pharmacological Targeting of BMP6-SMAD Mediated Hepcidin Expression Does Not Improve the Outcome of Systemic Infections With Intra-Or Extracellular Gram-Negative Bacteria in Mice |
| title_full_unstemmed | Pharmacological Targeting of BMP6-SMAD Mediated Hepcidin Expression Does Not Improve the Outcome of Systemic Infections With Intra-Or Extracellular Gram-Negative Bacteria in Mice |
| title_short | Pharmacological Targeting of BMP6-SMAD Mediated Hepcidin Expression Does Not Improve the Outcome of Systemic Infections With Intra-Or Extracellular Gram-Negative Bacteria in Mice |
| title_sort | pharmacological targeting of bmp6 smad mediated hepcidin expression does not improve the outcome of systemic infections with intra or extracellular gram negative bacteria in mice |
| topic | hepcidin inhibitor infection Gram-negative bacteria over-sulfated heparins LDN-193189 Salmonella |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2021.705087/full |
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