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 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. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Alexander Hoffmann [verfasserIn] Lara Valente de Souza [verfasserIn] Markus Seifert [verfasserIn] Laura von Raffay [verfasserIn] David Haschka [verfasserIn] Philipp Grubwieser [verfasserIn] Manuel Grander [verfasserIn] Anna-Maria Mitterstiller [verfasserIn] Manfred Nairz [verfasserIn] Maura Poli [verfasserIn] Günter Weiss [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	hepcidin inhibitor infection Gram-negative bacteria over-sulfated heparins LDN-193189 Salmonella

Übergeordnetes Werk:	In: Frontiers in Cellular and Infection Microbiology - Frontiers Media S.A., 2016, 11(2021)
Übergeordnetes Werk:	volume:11 ; year:2021

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fcimb.2021.705087

Katalog-ID:	DOAJ001547135

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520			\|a 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.
650		4	\|a hepcidin inhibitor
650		4	\|a infection
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650		4	\|a Salmonella
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allfields	10.3389/fcimb.2021.705087 doi (DE-627)DOAJ001547135 (DE-599)DOAJc302519a49e24bd787cddd5f6bdb8090 DE-627 ger DE-627 rakwb eng QR1-502 Alexander Hoffmann verfasserin aut 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 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. hepcidin inhibitor infection Gram-negative bacteria over-sulfated heparins LDN-193189 Salmonella Microbiology Alexander Hoffmann verfasserin aut Lara Valente de Souza verfasserin aut Lara Valente de Souza verfasserin aut Markus Seifert verfasserin aut Markus Seifert verfasserin aut Laura von Raffay verfasserin aut Laura von Raffay verfasserin aut David Haschka verfasserin aut Philipp Grubwieser verfasserin aut Manuel Grander verfasserin aut Anna-Maria Mitterstiller verfasserin aut Manfred Nairz verfasserin aut Maura Poli verfasserin aut Günter Weiss verfasserin aut Günter Weiss verfasserin aut In Frontiers in Cellular and Infection Microbiology Frontiers Media S.A., 2016 11(2021) (DE-627)664968554 (DE-600)2619676-1 22352988 nnns volume:11 year:2021 https://doi.org/10.3389/fcimb.2021.705087 kostenfrei https://doaj.org/article/c302519a49e24bd787cddd5f6bdb8090 kostenfrei https://www.frontiersin.org/articles/10.3389/fcimb.2021.705087/full kostenfrei https://doaj.org/toc/2235-2988 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021
spelling	10.3389/fcimb.2021.705087 doi (DE-627)DOAJ001547135 (DE-599)DOAJc302519a49e24bd787cddd5f6bdb8090 DE-627 ger DE-627 rakwb eng QR1-502 Alexander Hoffmann verfasserin aut 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 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. hepcidin inhibitor infection Gram-negative bacteria over-sulfated heparins LDN-193189 Salmonella Microbiology Alexander Hoffmann verfasserin aut Lara Valente de Souza verfasserin aut Lara Valente de Souza verfasserin aut Markus Seifert verfasserin aut Markus Seifert verfasserin aut Laura von Raffay verfasserin aut Laura von Raffay verfasserin aut David Haschka verfasserin aut Philipp Grubwieser verfasserin aut Manuel Grander verfasserin aut Anna-Maria Mitterstiller verfasserin aut Manfred Nairz verfasserin aut Maura Poli verfasserin aut Günter Weiss verfasserin aut Günter Weiss verfasserin aut In Frontiers in Cellular and Infection Microbiology Frontiers Media S.A., 2016 11(2021) (DE-627)664968554 (DE-600)2619676-1 22352988 nnns volume:11 year:2021 https://doi.org/10.3389/fcimb.2021.705087 kostenfrei https://doaj.org/article/c302519a49e24bd787cddd5f6bdb8090 kostenfrei https://www.frontiersin.org/articles/10.3389/fcimb.2021.705087/full kostenfrei https://doaj.org/toc/2235-2988 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021
allfields_unstemmed	10.3389/fcimb.2021.705087 doi (DE-627)DOAJ001547135 (DE-599)DOAJc302519a49e24bd787cddd5f6bdb8090 DE-627 ger DE-627 rakwb eng QR1-502 Alexander Hoffmann verfasserin aut 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 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. hepcidin inhibitor infection Gram-negative bacteria over-sulfated heparins LDN-193189 Salmonella Microbiology Alexander Hoffmann verfasserin aut Lara Valente de Souza verfasserin aut Lara Valente de Souza verfasserin aut Markus Seifert verfasserin aut Markus Seifert verfasserin aut Laura von Raffay verfasserin aut Laura von Raffay verfasserin aut David Haschka verfasserin aut Philipp Grubwieser verfasserin aut Manuel Grander verfasserin aut Anna-Maria Mitterstiller verfasserin aut Manfred Nairz verfasserin aut Maura Poli verfasserin aut Günter Weiss verfasserin aut Günter Weiss verfasserin aut In Frontiers in Cellular and Infection Microbiology Frontiers Media S.A., 2016 11(2021) (DE-627)664968554 (DE-600)2619676-1 22352988 nnns volume:11 year:2021 https://doi.org/10.3389/fcimb.2021.705087 kostenfrei https://doaj.org/article/c302519a49e24bd787cddd5f6bdb8090 kostenfrei https://www.frontiersin.org/articles/10.3389/fcimb.2021.705087/full kostenfrei https://doaj.org/toc/2235-2988 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021
allfieldsGer	10.3389/fcimb.2021.705087 doi (DE-627)DOAJ001547135 (DE-599)DOAJc302519a49e24bd787cddd5f6bdb8090 DE-627 ger DE-627 rakwb eng QR1-502 Alexander Hoffmann verfasserin aut 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 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. hepcidin inhibitor infection Gram-negative bacteria over-sulfated heparins LDN-193189 Salmonella Microbiology Alexander Hoffmann verfasserin aut Lara Valente de Souza verfasserin aut Lara Valente de Souza verfasserin aut Markus Seifert verfasserin aut Markus Seifert verfasserin aut Laura von Raffay verfasserin aut Laura von Raffay verfasserin aut David Haschka verfasserin aut Philipp Grubwieser verfasserin aut Manuel Grander verfasserin aut Anna-Maria Mitterstiller verfasserin aut Manfred Nairz verfasserin aut Maura Poli verfasserin aut Günter Weiss verfasserin aut Günter Weiss verfasserin aut In Frontiers in Cellular and Infection Microbiology Frontiers Media S.A., 2016 11(2021) (DE-627)664968554 (DE-600)2619676-1 22352988 nnns volume:11 year:2021 https://doi.org/10.3389/fcimb.2021.705087 kostenfrei https://doaj.org/article/c302519a49e24bd787cddd5f6bdb8090 kostenfrei https://www.frontiersin.org/articles/10.3389/fcimb.2021.705087/full kostenfrei https://doaj.org/toc/2235-2988 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021
allfieldsSound	10.3389/fcimb.2021.705087 doi (DE-627)DOAJ001547135 (DE-599)DOAJc302519a49e24bd787cddd5f6bdb8090 DE-627 ger DE-627 rakwb eng QR1-502 Alexander Hoffmann verfasserin aut 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 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. hepcidin inhibitor infection Gram-negative bacteria over-sulfated heparins LDN-193189 Salmonella Microbiology Alexander Hoffmann verfasserin aut Lara Valente de Souza verfasserin aut Lara Valente de Souza verfasserin aut Markus Seifert verfasserin aut Markus Seifert verfasserin aut Laura von Raffay verfasserin aut Laura von Raffay verfasserin aut David Haschka verfasserin aut Philipp Grubwieser verfasserin aut Manuel Grander verfasserin aut Anna-Maria Mitterstiller verfasserin aut Manfred Nairz verfasserin aut Maura Poli verfasserin aut Günter Weiss verfasserin aut Günter Weiss verfasserin aut In Frontiers in Cellular and Infection Microbiology Frontiers Media S.A., 2016 11(2021) (DE-627)664968554 (DE-600)2619676-1 22352988 nnns volume:11 year:2021 https://doi.org/10.3389/fcimb.2021.705087 kostenfrei https://doaj.org/article/c302519a49e24bd787cddd5f6bdb8090 kostenfrei https://www.frontiersin.org/articles/10.3389/fcimb.2021.705087/full kostenfrei https://doaj.org/toc/2235-2988 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021
language	English
source	In Frontiers in Cellular and Infection Microbiology 11(2021) volume:11 year:2021
sourceStr	In Frontiers in Cellular and Infection Microbiology 11(2021) volume:11 year:2021
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	hepcidin inhibitor infection Gram-negative bacteria over-sulfated heparins LDN-193189 Salmonella Microbiology
isfreeaccess_bool	true
container_title	Frontiers in Cellular and Infection Microbiology
authorswithroles_txt_mv	Alexander Hoffmann @@aut@@ Lara Valente de Souza @@aut@@ Markus Seifert @@aut@@ Laura von Raffay @@aut@@ David Haschka @@aut@@ Philipp Grubwieser @@aut@@ Manuel Grander @@aut@@ Anna-Maria Mitterstiller @@aut@@ Manfred Nairz @@aut@@ Maura Poli @@aut@@ Günter Weiss @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	664968554
id	DOAJ001547135
language_de	englisch
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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. 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callnumber-first	Q - Science
author	Alexander Hoffmann
spellingShingle	Alexander Hoffmann misc QR1-502 misc hepcidin inhibitor misc infection misc Gram-negative bacteria misc over-sulfated heparins misc LDN-193189 misc Salmonella misc Microbiology 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
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topic_title	QR1-502 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 hepcidin inhibitor infection Gram-negative bacteria over-sulfated heparins LDN-193189 Salmonella
topic	misc QR1-502 misc hepcidin inhibitor misc infection misc Gram-negative bacteria misc over-sulfated heparins misc LDN-193189 misc Salmonella misc Microbiology
topic_unstemmed	misc QR1-502 misc hepcidin inhibitor misc infection misc Gram-negative bacteria misc over-sulfated heparins misc LDN-193189 misc Salmonella misc Microbiology
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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
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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
author_sort	Alexander Hoffmann
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author_browse	Alexander Hoffmann Lara Valente de Souza Markus Seifert Laura von Raffay David Haschka Philipp Grubwieser Manuel Grander Anna-Maria Mitterstiller Manfred Nairz Maura Poli Günter Weiss
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doi_str_mv	10.3389/fcimb.2021.705087
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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
callnumber	QR1-502
title_auth	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
abstract	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.
abstractGer	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.
abstract_unstemmed	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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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
url	https://doi.org/10.3389/fcimb.2021.705087 https://doaj.org/article/c302519a49e24bd787cddd5f6bdb8090 https://www.frontiersin.org/articles/10.3389/fcimb.2021.705087/full https://doaj.org/toc/2235-2988
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author2	Alexander Hoffmann Lara Valente de Souza Markus Seifert Laura von Raffay David Haschka Philipp Grubwieser Manuel Grander Anna-Maria Mitterstiller Manfred Nairz Maura Poli Günter Weiss
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up_date	2024-07-03T21:04:58.316Z
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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

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