Intranasal delivery of a small-molecule ErbB inhibitor promotes recovery from acute and late-stage CNS inflammation
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in M...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Mathias Linnerbauer [verfasserIn] Lena Lößlein [verfasserIn] Oliver Vandrey [verfasserIn] Thanos Tsaktanis [verfasserIn] Alexander Beer [verfasserIn] Ulrike J. Naumann [verfasserIn] Franziska Panier [verfasserIn] Tobias Beyer [verfasserIn] Lucy Nirschl [verfasserIn] Joji B. Kuramatsu [verfasserIn] Jürgen Winkler [verfasserIn] Francisco J. Quintana [verfasserIn] Veit Rothhammer [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
In: JCI Insight - American Society for Clinical investigation, 2020, 7(2022), 7 |
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| Übergeordnetes Werk: |
volume:7 ; year:2022 ; number:7 |
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DOAJ042630789 |
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| 520 | |a Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in MS and its animal models have described astrocytes and their spatial and functional heterogeneity as important cellular determinants of chronic disease. We combined CNS single-cell transcriptome data and small-molecule screens in primary mouse and human astrocytes to identify glial interactions, which could be targeted by repurposing FDA-approved small-molecule modulators for the treatment of acute and late-stage CNS inflammation. Using hierarchical in vitro and in vivo validation studies, we demonstrate that among selected pathways, blockade of ErbB by the tyrosine kinase inhibitor afatinib efficiently mitigates proinflammatory astrocyte polarization and promotes tissue-regenerative functions. We found that i.n. delivery of afatinib during acute and late-stage CNS inflammation ameliorates disease severity by reducing monocyte infiltration and axonal degeneration while increasing oligodendrocyte proliferation. We used unbiased screening approaches of astrocyte interactions to identify ErbB signaling and its modulation by afatinib as a potential therapeutic strategy for acute and chronic stages of autoimmune CNS inflammation. | ||
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(DE-627)DOAJ042630789 (DE-599)DOAJ7bdc9d38b2d8495e858ff11e9bf9ca2f DE-627 ger DE-627 rakwb eng Mathias Linnerbauer verfasserin aut Intranasal delivery of a small-molecule ErbB inhibitor promotes recovery from acute and late-stage CNS inflammation 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in MS and its animal models have described astrocytes and their spatial and functional heterogeneity as important cellular determinants of chronic disease. We combined CNS single-cell transcriptome data and small-molecule screens in primary mouse and human astrocytes to identify glial interactions, which could be targeted by repurposing FDA-approved small-molecule modulators for the treatment of acute and late-stage CNS inflammation. Using hierarchical in vitro and in vivo validation studies, we demonstrate that among selected pathways, blockade of ErbB by the tyrosine kinase inhibitor afatinib efficiently mitigates proinflammatory astrocyte polarization and promotes tissue-regenerative functions. We found that i.n. delivery of afatinib during acute and late-stage CNS inflammation ameliorates disease severity by reducing monocyte infiltration and axonal degeneration while increasing oligodendrocyte proliferation. We used unbiased screening approaches of astrocyte interactions to identify ErbB signaling and its modulation by afatinib as a potential therapeutic strategy for acute and chronic stages of autoimmune CNS inflammation. Autoimmunity Neuroscience Medicine R Lena Lößlein verfasserin aut Oliver Vandrey verfasserin aut Thanos Tsaktanis verfasserin aut Alexander Beer verfasserin aut Ulrike J. Naumann verfasserin aut Franziska Panier verfasserin aut Tobias Beyer verfasserin aut Lucy Nirschl verfasserin aut Joji B. Kuramatsu verfasserin aut Jürgen Winkler verfasserin aut Francisco J. Quintana verfasserin aut Veit Rothhammer verfasserin aut In JCI Insight American Society for Clinical investigation, 2020 7(2022), 7 (DE-627)872610594 (DE-600)2874757-4 23793708 nnns volume:7 year:2022 number:7 https://doaj.org/article/7bdc9d38b2d8495e858ff11e9bf9ca2f kostenfrei https://doi.org/10.1172/jci.insight.154824 kostenfrei https://doaj.org/toc/2379-3708 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA 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_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 7 2022 7 |
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(DE-627)DOAJ042630789 (DE-599)DOAJ7bdc9d38b2d8495e858ff11e9bf9ca2f DE-627 ger DE-627 rakwb eng Mathias Linnerbauer verfasserin aut Intranasal delivery of a small-molecule ErbB inhibitor promotes recovery from acute and late-stage CNS inflammation 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in MS and its animal models have described astrocytes and their spatial and functional heterogeneity as important cellular determinants of chronic disease. We combined CNS single-cell transcriptome data and small-molecule screens in primary mouse and human astrocytes to identify glial interactions, which could be targeted by repurposing FDA-approved small-molecule modulators for the treatment of acute and late-stage CNS inflammation. Using hierarchical in vitro and in vivo validation studies, we demonstrate that among selected pathways, blockade of ErbB by the tyrosine kinase inhibitor afatinib efficiently mitigates proinflammatory astrocyte polarization and promotes tissue-regenerative functions. We found that i.n. delivery of afatinib during acute and late-stage CNS inflammation ameliorates disease severity by reducing monocyte infiltration and axonal degeneration while increasing oligodendrocyte proliferation. We used unbiased screening approaches of astrocyte interactions to identify ErbB signaling and its modulation by afatinib as a potential therapeutic strategy for acute and chronic stages of autoimmune CNS inflammation. Autoimmunity Neuroscience Medicine R Lena Lößlein verfasserin aut Oliver Vandrey verfasserin aut Thanos Tsaktanis verfasserin aut Alexander Beer verfasserin aut Ulrike J. Naumann verfasserin aut Franziska Panier verfasserin aut Tobias Beyer verfasserin aut Lucy Nirschl verfasserin aut Joji B. Kuramatsu verfasserin aut Jürgen Winkler verfasserin aut Francisco J. Quintana verfasserin aut Veit Rothhammer verfasserin aut In JCI Insight American Society for Clinical investigation, 2020 7(2022), 7 (DE-627)872610594 (DE-600)2874757-4 23793708 nnns volume:7 year:2022 number:7 https://doaj.org/article/7bdc9d38b2d8495e858ff11e9bf9ca2f kostenfrei https://doi.org/10.1172/jci.insight.154824 kostenfrei https://doaj.org/toc/2379-3708 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA 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_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 7 2022 7 |
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(DE-627)DOAJ042630789 (DE-599)DOAJ7bdc9d38b2d8495e858ff11e9bf9ca2f DE-627 ger DE-627 rakwb eng Mathias Linnerbauer verfasserin aut Intranasal delivery of a small-molecule ErbB inhibitor promotes recovery from acute and late-stage CNS inflammation 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in MS and its animal models have described astrocytes and their spatial and functional heterogeneity as important cellular determinants of chronic disease. We combined CNS single-cell transcriptome data and small-molecule screens in primary mouse and human astrocytes to identify glial interactions, which could be targeted by repurposing FDA-approved small-molecule modulators for the treatment of acute and late-stage CNS inflammation. Using hierarchical in vitro and in vivo validation studies, we demonstrate that among selected pathways, blockade of ErbB by the tyrosine kinase inhibitor afatinib efficiently mitigates proinflammatory astrocyte polarization and promotes tissue-regenerative functions. We found that i.n. delivery of afatinib during acute and late-stage CNS inflammation ameliorates disease severity by reducing monocyte infiltration and axonal degeneration while increasing oligodendrocyte proliferation. We used unbiased screening approaches of astrocyte interactions to identify ErbB signaling and its modulation by afatinib as a potential therapeutic strategy for acute and chronic stages of autoimmune CNS inflammation. Autoimmunity Neuroscience Medicine R Lena Lößlein verfasserin aut Oliver Vandrey verfasserin aut Thanos Tsaktanis verfasserin aut Alexander Beer verfasserin aut Ulrike J. Naumann verfasserin aut Franziska Panier verfasserin aut Tobias Beyer verfasserin aut Lucy Nirschl verfasserin aut Joji B. Kuramatsu verfasserin aut Jürgen Winkler verfasserin aut Francisco J. Quintana verfasserin aut Veit Rothhammer verfasserin aut In JCI Insight American Society for Clinical investigation, 2020 7(2022), 7 (DE-627)872610594 (DE-600)2874757-4 23793708 nnns volume:7 year:2022 number:7 https://doaj.org/article/7bdc9d38b2d8495e858ff11e9bf9ca2f kostenfrei https://doi.org/10.1172/jci.insight.154824 kostenfrei https://doaj.org/toc/2379-3708 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA 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_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 7 2022 7 |
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(DE-627)DOAJ042630789 (DE-599)DOAJ7bdc9d38b2d8495e858ff11e9bf9ca2f DE-627 ger DE-627 rakwb eng Mathias Linnerbauer verfasserin aut Intranasal delivery of a small-molecule ErbB inhibitor promotes recovery from acute and late-stage CNS inflammation 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in MS and its animal models have described astrocytes and their spatial and functional heterogeneity as important cellular determinants of chronic disease. We combined CNS single-cell transcriptome data and small-molecule screens in primary mouse and human astrocytes to identify glial interactions, which could be targeted by repurposing FDA-approved small-molecule modulators for the treatment of acute and late-stage CNS inflammation. Using hierarchical in vitro and in vivo validation studies, we demonstrate that among selected pathways, blockade of ErbB by the tyrosine kinase inhibitor afatinib efficiently mitigates proinflammatory astrocyte polarization and promotes tissue-regenerative functions. We found that i.n. delivery of afatinib during acute and late-stage CNS inflammation ameliorates disease severity by reducing monocyte infiltration and axonal degeneration while increasing oligodendrocyte proliferation. We used unbiased screening approaches of astrocyte interactions to identify ErbB signaling and its modulation by afatinib as a potential therapeutic strategy for acute and chronic stages of autoimmune CNS inflammation. Autoimmunity Neuroscience Medicine R Lena Lößlein verfasserin aut Oliver Vandrey verfasserin aut Thanos Tsaktanis verfasserin aut Alexander Beer verfasserin aut Ulrike J. Naumann verfasserin aut Franziska Panier verfasserin aut Tobias Beyer verfasserin aut Lucy Nirschl verfasserin aut Joji B. Kuramatsu verfasserin aut Jürgen Winkler verfasserin aut Francisco J. Quintana verfasserin aut Veit Rothhammer verfasserin aut In JCI Insight American Society for Clinical investigation, 2020 7(2022), 7 (DE-627)872610594 (DE-600)2874757-4 23793708 nnns volume:7 year:2022 number:7 https://doaj.org/article/7bdc9d38b2d8495e858ff11e9bf9ca2f kostenfrei https://doi.org/10.1172/jci.insight.154824 kostenfrei https://doaj.org/toc/2379-3708 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA 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_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 7 2022 7 |
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Intranasal delivery of a small-molecule ErbB inhibitor promotes recovery from acute and late-stage CNS inflammation |
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Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in MS and its animal models have described astrocytes and their spatial and functional heterogeneity as important cellular determinants of chronic disease. We combined CNS single-cell transcriptome data and small-molecule screens in primary mouse and human astrocytes to identify glial interactions, which could be targeted by repurposing FDA-approved small-molecule modulators for the treatment of acute and late-stage CNS inflammation. Using hierarchical in vitro and in vivo validation studies, we demonstrate that among selected pathways, blockade of ErbB by the tyrosine kinase inhibitor afatinib efficiently mitigates proinflammatory astrocyte polarization and promotes tissue-regenerative functions. We found that i.n. delivery of afatinib during acute and late-stage CNS inflammation ameliorates disease severity by reducing monocyte infiltration and axonal degeneration while increasing oligodendrocyte proliferation. We used unbiased screening approaches of astrocyte interactions to identify ErbB signaling and its modulation by afatinib as a potential therapeutic strategy for acute and chronic stages of autoimmune CNS inflammation. |
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Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in MS and its animal models have described astrocytes and their spatial and functional heterogeneity as important cellular determinants of chronic disease. We combined CNS single-cell transcriptome data and small-molecule screens in primary mouse and human astrocytes to identify glial interactions, which could be targeted by repurposing FDA-approved small-molecule modulators for the treatment of acute and late-stage CNS inflammation. Using hierarchical in vitro and in vivo validation studies, we demonstrate that among selected pathways, blockade of ErbB by the tyrosine kinase inhibitor afatinib efficiently mitigates proinflammatory astrocyte polarization and promotes tissue-regenerative functions. We found that i.n. delivery of afatinib during acute and late-stage CNS inflammation ameliorates disease severity by reducing monocyte infiltration and axonal degeneration while increasing oligodendrocyte proliferation. We used unbiased screening approaches of astrocyte interactions to identify ErbB signaling and its modulation by afatinib as a potential therapeutic strategy for acute and chronic stages of autoimmune CNS inflammation. |
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Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in MS and its animal models have described astrocytes and their spatial and functional heterogeneity as important cellular determinants of chronic disease. We combined CNS single-cell transcriptome data and small-molecule screens in primary mouse and human astrocytes to identify glial interactions, which could be targeted by repurposing FDA-approved small-molecule modulators for the treatment of acute and late-stage CNS inflammation. Using hierarchical in vitro and in vivo validation studies, we demonstrate that among selected pathways, blockade of ErbB by the tyrosine kinase inhibitor afatinib efficiently mitigates proinflammatory astrocyte polarization and promotes tissue-regenerative functions. We found that i.n. delivery of afatinib during acute and late-stage CNS inflammation ameliorates disease severity by reducing monocyte infiltration and axonal degeneration while increasing oligodendrocyte proliferation. We used unbiased screening approaches of astrocyte interactions to identify ErbB signaling and its modulation by afatinib as a potential therapeutic strategy for acute and chronic stages of autoimmune CNS inflammation. |
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