Genetic targeting or pharmacological inhibition of galectin-3 dampens microglia reactivity and delays retinal degeneration
Background Dysfunctional humoral and cellular innate immunity are key components in the development and progression of age-related macular degeneration (AMD). Specifically, chronically activated microglia and their disturbed regulatory system contribute to retinal degeneration. Galectin-3, a β-galac...
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Tabel, Mona [verfasserIn] |
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E-Artikel |
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Englisch |
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2022 |
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© The Author(s) 2022 |
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Enthalten in: Journal of neuroinflammation - London : BioMed Central, 2004, 19(2022), 1 vom: 17. Sept. |
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| Übergeordnetes Werk: |
volume:19 ; year:2022 ; number:1 ; day:17 ; month:09 |
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| DOI / URN: |
10.1186/s12974-022-02589-6 |
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SPR05099977X |
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| 520 | |a Background Dysfunctional humoral and cellular innate immunity are key components in the development and progression of age-related macular degeneration (AMD). Specifically, chronically activated microglia and their disturbed regulatory system contribute to retinal degeneration. Galectin-3, a β-galactose binding protein, is a potent driver of macrophage and microglia activation and has been implicated in neuroinflammation, including neurodegenerative diseases of the brain. Here, we hypothesized that genetic deficiency of galectin-3 or its modulation via TD139 dampens mononuclear phagocyte reactivity and delays retinal degeneration. Methods Galectin-3 expression in AMD patients was analyzed by immunohistochemical stainings. Galectin-3 knockout and BALB/cJ mice were exposed to white bright light with an intensity of 15,000 lux for 1 h and $ Cx3cr1^{GFP/+} $ mice to focal blue light of 50,000 lux for 10 min. BALB/cJ and $ Cx3cr1^{GFP/+} $ mice received intraperitoneal injections of 15 mg/kg TD139 or vehicle for five consecutive days, starting one day prior to light exposure. The effects of galectin-3 deficiency or inhibition on microglia were analyzed by immunohistochemical stainings and in situ hybridization of retinal sections and flat mounts. Pro-inflammatory cytokine levels in the retina and retinal pigment epithelium (RPE) were quantified by qRT-PCR and transcriptomic changes were analyzed by RNA-sequencing. Retinal thickness and structure were evaluated by optical coherence tomography. Results We found that galectin-3 expression was strongly upregulated in reactive retinal mononuclear phagocytes of AMD patients and in the two related mouse models of light-induced retinal degeneration. The experimental in vivo data further showed that specific targeting of galectin-3 by genetic knockout or administration of the small-molecule inhibitor TD139 reduced microglia reactivity and delayed retinal damage in both light damage conditions. Conclusion This study defines galectin-3 as a potent driver of retinal degeneration and highlights the protein as a drug target for ocular immunomodulatory therapies. | ||
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| 650 | 4 | |a Galectin-3 inhibition |7 (dpeaa)DE-He213 | |
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| 650 | 4 | |a Microglia |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Retinal degeneration |7 (dpeaa)DE-He213 | |
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| 700 | 1 | |a Wolf, Anne |4 aut | |
| 700 | 1 | |a Szczepan, Manon |4 aut | |
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| 700 | 1 | |a Moehle, Christoph |4 aut | |
| 700 | 1 | |a Chen, Mei |4 aut | |
| 700 | 1 | |a Langmann, Thomas |4 aut | |
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10.1186/s12974-022-02589-6 doi (DE-627)SPR05099977X (SPR)s12974-022-02589-6-e DE-627 ger DE-627 rakwb eng Tabel, Mona verfasserin aut Genetic targeting or pharmacological inhibition of galectin-3 dampens microglia reactivity and delays retinal degeneration 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Dysfunctional humoral and cellular innate immunity are key components in the development and progression of age-related macular degeneration (AMD). Specifically, chronically activated microglia and their disturbed regulatory system contribute to retinal degeneration. Galectin-3, a β-galactose binding protein, is a potent driver of macrophage and microglia activation and has been implicated in neuroinflammation, including neurodegenerative diseases of the brain. Here, we hypothesized that genetic deficiency of galectin-3 or its modulation via TD139 dampens mononuclear phagocyte reactivity and delays retinal degeneration. Methods Galectin-3 expression in AMD patients was analyzed by immunohistochemical stainings. Galectin-3 knockout and BALB/cJ mice were exposed to white bright light with an intensity of 15,000 lux for 1 h and $ Cx3cr1^{GFP/+} $ mice to focal blue light of 50,000 lux for 10 min. BALB/cJ and $ Cx3cr1^{GFP/+} $ mice received intraperitoneal injections of 15 mg/kg TD139 or vehicle for five consecutive days, starting one day prior to light exposure. The effects of galectin-3 deficiency or inhibition on microglia were analyzed by immunohistochemical stainings and in situ hybridization of retinal sections and flat mounts. Pro-inflammatory cytokine levels in the retina and retinal pigment epithelium (RPE) were quantified by qRT-PCR and transcriptomic changes were analyzed by RNA-sequencing. Retinal thickness and structure were evaluated by optical coherence tomography. Results We found that galectin-3 expression was strongly upregulated in reactive retinal mononuclear phagocytes of AMD patients and in the two related mouse models of light-induced retinal degeneration. The experimental in vivo data further showed that specific targeting of galectin-3 by genetic knockout or administration of the small-molecule inhibitor TD139 reduced microglia reactivity and delayed retinal damage in both light damage conditions. Conclusion This study defines galectin-3 as a potent driver of retinal degeneration and highlights the protein as a drug target for ocular immunomodulatory therapies. Galectin-3 deficiency (dpeaa)DE-He213 Galectin-3 inhibition (dpeaa)DE-He213 TD139 (dpeaa)DE-He213 Microglia (dpeaa)DE-He213 Retinal degeneration (dpeaa)DE-He213 Light damage (dpeaa)DE-He213 Wolf, Anne aut Szczepan, Manon aut Xu, Heping aut Jägle, Herbert aut Moehle, Christoph aut Chen, Mei aut Langmann, Thomas aut Enthalten in Journal of neuroinflammation London : BioMed Central, 2004 19(2022), 1 vom: 17. Sept. (DE-627)391784781 (DE-600)2156455-3 1742-2094 nnns volume:19 year:2022 number:1 day:17 month:09 https://dx.doi.org/10.1186/s12974-022-02589-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER 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_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 19 2022 1 17 09 |
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10.1186/s12974-022-02589-6 doi (DE-627)SPR05099977X (SPR)s12974-022-02589-6-e DE-627 ger DE-627 rakwb eng Tabel, Mona verfasserin aut Genetic targeting or pharmacological inhibition of galectin-3 dampens microglia reactivity and delays retinal degeneration 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Dysfunctional humoral and cellular innate immunity are key components in the development and progression of age-related macular degeneration (AMD). Specifically, chronically activated microglia and their disturbed regulatory system contribute to retinal degeneration. Galectin-3, a β-galactose binding protein, is a potent driver of macrophage and microglia activation and has been implicated in neuroinflammation, including neurodegenerative diseases of the brain. Here, we hypothesized that genetic deficiency of galectin-3 or its modulation via TD139 dampens mononuclear phagocyte reactivity and delays retinal degeneration. Methods Galectin-3 expression in AMD patients was analyzed by immunohistochemical stainings. Galectin-3 knockout and BALB/cJ mice were exposed to white bright light with an intensity of 15,000 lux for 1 h and $ Cx3cr1^{GFP/+} $ mice to focal blue light of 50,000 lux for 10 min. BALB/cJ and $ Cx3cr1^{GFP/+} $ mice received intraperitoneal injections of 15 mg/kg TD139 or vehicle for five consecutive days, starting one day prior to light exposure. The effects of galectin-3 deficiency or inhibition on microglia were analyzed by immunohistochemical stainings and in situ hybridization of retinal sections and flat mounts. Pro-inflammatory cytokine levels in the retina and retinal pigment epithelium (RPE) were quantified by qRT-PCR and transcriptomic changes were analyzed by RNA-sequencing. Retinal thickness and structure were evaluated by optical coherence tomography. Results We found that galectin-3 expression was strongly upregulated in reactive retinal mononuclear phagocytes of AMD patients and in the two related mouse models of light-induced retinal degeneration. The experimental in vivo data further showed that specific targeting of galectin-3 by genetic knockout or administration of the small-molecule inhibitor TD139 reduced microglia reactivity and delayed retinal damage in both light damage conditions. Conclusion This study defines galectin-3 as a potent driver of retinal degeneration and highlights the protein as a drug target for ocular immunomodulatory therapies. Galectin-3 deficiency (dpeaa)DE-He213 Galectin-3 inhibition (dpeaa)DE-He213 TD139 (dpeaa)DE-He213 Microglia (dpeaa)DE-He213 Retinal degeneration (dpeaa)DE-He213 Light damage (dpeaa)DE-He213 Wolf, Anne aut Szczepan, Manon aut Xu, Heping aut Jägle, Herbert aut Moehle, Christoph aut Chen, Mei aut Langmann, Thomas aut Enthalten in Journal of neuroinflammation London : BioMed Central, 2004 19(2022), 1 vom: 17. Sept. (DE-627)391784781 (DE-600)2156455-3 1742-2094 nnns volume:19 year:2022 number:1 day:17 month:09 https://dx.doi.org/10.1186/s12974-022-02589-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER 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_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 19 2022 1 17 09 |
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10.1186/s12974-022-02589-6 doi (DE-627)SPR05099977X (SPR)s12974-022-02589-6-e DE-627 ger DE-627 rakwb eng Tabel, Mona verfasserin aut Genetic targeting or pharmacological inhibition of galectin-3 dampens microglia reactivity and delays retinal degeneration 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Dysfunctional humoral and cellular innate immunity are key components in the development and progression of age-related macular degeneration (AMD). Specifically, chronically activated microglia and their disturbed regulatory system contribute to retinal degeneration. Galectin-3, a β-galactose binding protein, is a potent driver of macrophage and microglia activation and has been implicated in neuroinflammation, including neurodegenerative diseases of the brain. Here, we hypothesized that genetic deficiency of galectin-3 or its modulation via TD139 dampens mononuclear phagocyte reactivity and delays retinal degeneration. Methods Galectin-3 expression in AMD patients was analyzed by immunohistochemical stainings. Galectin-3 knockout and BALB/cJ mice were exposed to white bright light with an intensity of 15,000 lux for 1 h and $ Cx3cr1^{GFP/+} $ mice to focal blue light of 50,000 lux for 10 min. BALB/cJ and $ Cx3cr1^{GFP/+} $ mice received intraperitoneal injections of 15 mg/kg TD139 or vehicle for five consecutive days, starting one day prior to light exposure. The effects of galectin-3 deficiency or inhibition on microglia were analyzed by immunohistochemical stainings and in situ hybridization of retinal sections and flat mounts. Pro-inflammatory cytokine levels in the retina and retinal pigment epithelium (RPE) were quantified by qRT-PCR and transcriptomic changes were analyzed by RNA-sequencing. Retinal thickness and structure were evaluated by optical coherence tomography. Results We found that galectin-3 expression was strongly upregulated in reactive retinal mononuclear phagocytes of AMD patients and in the two related mouse models of light-induced retinal degeneration. The experimental in vivo data further showed that specific targeting of galectin-3 by genetic knockout or administration of the small-molecule inhibitor TD139 reduced microglia reactivity and delayed retinal damage in both light damage conditions. Conclusion This study defines galectin-3 as a potent driver of retinal degeneration and highlights the protein as a drug target for ocular immunomodulatory therapies. Galectin-3 deficiency (dpeaa)DE-He213 Galectin-3 inhibition (dpeaa)DE-He213 TD139 (dpeaa)DE-He213 Microglia (dpeaa)DE-He213 Retinal degeneration (dpeaa)DE-He213 Light damage (dpeaa)DE-He213 Wolf, Anne aut Szczepan, Manon aut Xu, Heping aut Jägle, Herbert aut Moehle, Christoph aut Chen, Mei aut Langmann, Thomas aut Enthalten in Journal of neuroinflammation London : BioMed Central, 2004 19(2022), 1 vom: 17. Sept. (DE-627)391784781 (DE-600)2156455-3 1742-2094 nnns volume:19 year:2022 number:1 day:17 month:09 https://dx.doi.org/10.1186/s12974-022-02589-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER 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_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 19 2022 1 17 09 |
| allfieldsGer |
10.1186/s12974-022-02589-6 doi (DE-627)SPR05099977X (SPR)s12974-022-02589-6-e DE-627 ger DE-627 rakwb eng Tabel, Mona verfasserin aut Genetic targeting or pharmacological inhibition of galectin-3 dampens microglia reactivity and delays retinal degeneration 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Dysfunctional humoral and cellular innate immunity are key components in the development and progression of age-related macular degeneration (AMD). Specifically, chronically activated microglia and their disturbed regulatory system contribute to retinal degeneration. Galectin-3, a β-galactose binding protein, is a potent driver of macrophage and microglia activation and has been implicated in neuroinflammation, including neurodegenerative diseases of the brain. Here, we hypothesized that genetic deficiency of galectin-3 or its modulation via TD139 dampens mononuclear phagocyte reactivity and delays retinal degeneration. Methods Galectin-3 expression in AMD patients was analyzed by immunohistochemical stainings. Galectin-3 knockout and BALB/cJ mice were exposed to white bright light with an intensity of 15,000 lux for 1 h and $ Cx3cr1^{GFP/+} $ mice to focal blue light of 50,000 lux for 10 min. BALB/cJ and $ Cx3cr1^{GFP/+} $ mice received intraperitoneal injections of 15 mg/kg TD139 or vehicle for five consecutive days, starting one day prior to light exposure. The effects of galectin-3 deficiency or inhibition on microglia were analyzed by immunohistochemical stainings and in situ hybridization of retinal sections and flat mounts. Pro-inflammatory cytokine levels in the retina and retinal pigment epithelium (RPE) were quantified by qRT-PCR and transcriptomic changes were analyzed by RNA-sequencing. Retinal thickness and structure were evaluated by optical coherence tomography. Results We found that galectin-3 expression was strongly upregulated in reactive retinal mononuclear phagocytes of AMD patients and in the two related mouse models of light-induced retinal degeneration. The experimental in vivo data further showed that specific targeting of galectin-3 by genetic knockout or administration of the small-molecule inhibitor TD139 reduced microglia reactivity and delayed retinal damage in both light damage conditions. Conclusion This study defines galectin-3 as a potent driver of retinal degeneration and highlights the protein as a drug target for ocular immunomodulatory therapies. Galectin-3 deficiency (dpeaa)DE-He213 Galectin-3 inhibition (dpeaa)DE-He213 TD139 (dpeaa)DE-He213 Microglia (dpeaa)DE-He213 Retinal degeneration (dpeaa)DE-He213 Light damage (dpeaa)DE-He213 Wolf, Anne aut Szczepan, Manon aut Xu, Heping aut Jägle, Herbert aut Moehle, Christoph aut Chen, Mei aut Langmann, Thomas aut Enthalten in Journal of neuroinflammation London : BioMed Central, 2004 19(2022), 1 vom: 17. Sept. (DE-627)391784781 (DE-600)2156455-3 1742-2094 nnns volume:19 year:2022 number:1 day:17 month:09 https://dx.doi.org/10.1186/s12974-022-02589-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER 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_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 19 2022 1 17 09 |
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10.1186/s12974-022-02589-6 doi (DE-627)SPR05099977X (SPR)s12974-022-02589-6-e DE-627 ger DE-627 rakwb eng Tabel, Mona verfasserin aut Genetic targeting or pharmacological inhibition of galectin-3 dampens microglia reactivity and delays retinal degeneration 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background Dysfunctional humoral and cellular innate immunity are key components in the development and progression of age-related macular degeneration (AMD). Specifically, chronically activated microglia and their disturbed regulatory system contribute to retinal degeneration. Galectin-3, a β-galactose binding protein, is a potent driver of macrophage and microglia activation and has been implicated in neuroinflammation, including neurodegenerative diseases of the brain. Here, we hypothesized that genetic deficiency of galectin-3 or its modulation via TD139 dampens mononuclear phagocyte reactivity and delays retinal degeneration. Methods Galectin-3 expression in AMD patients was analyzed by immunohistochemical stainings. Galectin-3 knockout and BALB/cJ mice were exposed to white bright light with an intensity of 15,000 lux for 1 h and $ Cx3cr1^{GFP/+} $ mice to focal blue light of 50,000 lux for 10 min. BALB/cJ and $ Cx3cr1^{GFP/+} $ mice received intraperitoneal injections of 15 mg/kg TD139 or vehicle for five consecutive days, starting one day prior to light exposure. The effects of galectin-3 deficiency or inhibition on microglia were analyzed by immunohistochemical stainings and in situ hybridization of retinal sections and flat mounts. Pro-inflammatory cytokine levels in the retina and retinal pigment epithelium (RPE) were quantified by qRT-PCR and transcriptomic changes were analyzed by RNA-sequencing. Retinal thickness and structure were evaluated by optical coherence tomography. Results We found that galectin-3 expression was strongly upregulated in reactive retinal mononuclear phagocytes of AMD patients and in the two related mouse models of light-induced retinal degeneration. The experimental in vivo data further showed that specific targeting of galectin-3 by genetic knockout or administration of the small-molecule inhibitor TD139 reduced microglia reactivity and delayed retinal damage in both light damage conditions. Conclusion This study defines galectin-3 as a potent driver of retinal degeneration and highlights the protein as a drug target for ocular immunomodulatory therapies. Galectin-3 deficiency (dpeaa)DE-He213 Galectin-3 inhibition (dpeaa)DE-He213 TD139 (dpeaa)DE-He213 Microglia (dpeaa)DE-He213 Retinal degeneration (dpeaa)DE-He213 Light damage (dpeaa)DE-He213 Wolf, Anne aut Szczepan, Manon aut Xu, Heping aut Jägle, Herbert aut Moehle, Christoph aut Chen, Mei aut Langmann, Thomas aut Enthalten in Journal of neuroinflammation London : BioMed Central, 2004 19(2022), 1 vom: 17. Sept. (DE-627)391784781 (DE-600)2156455-3 1742-2094 nnns volume:19 year:2022 number:1 day:17 month:09 https://dx.doi.org/10.1186/s12974-022-02589-6 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER 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_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 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 19 2022 1 17 09 |
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Genetic targeting or pharmacological inhibition of galectin-3 dampens microglia reactivity and delays retinal degeneration |
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Background Dysfunctional humoral and cellular innate immunity are key components in the development and progression of age-related macular degeneration (AMD). Specifically, chronically activated microglia and their disturbed regulatory system contribute to retinal degeneration. Galectin-3, a β-galactose binding protein, is a potent driver of macrophage and microglia activation and has been implicated in neuroinflammation, including neurodegenerative diseases of the brain. Here, we hypothesized that genetic deficiency of galectin-3 or its modulation via TD139 dampens mononuclear phagocyte reactivity and delays retinal degeneration. Methods Galectin-3 expression in AMD patients was analyzed by immunohistochemical stainings. Galectin-3 knockout and BALB/cJ mice were exposed to white bright light with an intensity of 15,000 lux for 1 h and $ Cx3cr1^{GFP/+} $ mice to focal blue light of 50,000 lux for 10 min. BALB/cJ and $ Cx3cr1^{GFP/+} $ mice received intraperitoneal injections of 15 mg/kg TD139 or vehicle for five consecutive days, starting one day prior to light exposure. The effects of galectin-3 deficiency or inhibition on microglia were analyzed by immunohistochemical stainings and in situ hybridization of retinal sections and flat mounts. Pro-inflammatory cytokine levels in the retina and retinal pigment epithelium (RPE) were quantified by qRT-PCR and transcriptomic changes were analyzed by RNA-sequencing. Retinal thickness and structure were evaluated by optical coherence tomography. Results We found that galectin-3 expression was strongly upregulated in reactive retinal mononuclear phagocytes of AMD patients and in the two related mouse models of light-induced retinal degeneration. The experimental in vivo data further showed that specific targeting of galectin-3 by genetic knockout or administration of the small-molecule inhibitor TD139 reduced microglia reactivity and delayed retinal damage in both light damage conditions. Conclusion This study defines galectin-3 as a potent driver of retinal degeneration and highlights the protein as a drug target for ocular immunomodulatory therapies. © The Author(s) 2022 |
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Background Dysfunctional humoral and cellular innate immunity are key components in the development and progression of age-related macular degeneration (AMD). Specifically, chronically activated microglia and their disturbed regulatory system contribute to retinal degeneration. Galectin-3, a β-galactose binding protein, is a potent driver of macrophage and microglia activation and has been implicated in neuroinflammation, including neurodegenerative diseases of the brain. Here, we hypothesized that genetic deficiency of galectin-3 or its modulation via TD139 dampens mononuclear phagocyte reactivity and delays retinal degeneration. Methods Galectin-3 expression in AMD patients was analyzed by immunohistochemical stainings. Galectin-3 knockout and BALB/cJ mice were exposed to white bright light with an intensity of 15,000 lux for 1 h and $ Cx3cr1^{GFP/+} $ mice to focal blue light of 50,000 lux for 10 min. BALB/cJ and $ Cx3cr1^{GFP/+} $ mice received intraperitoneal injections of 15 mg/kg TD139 or vehicle for five consecutive days, starting one day prior to light exposure. The effects of galectin-3 deficiency or inhibition on microglia were analyzed by immunohistochemical stainings and in situ hybridization of retinal sections and flat mounts. Pro-inflammatory cytokine levels in the retina and retinal pigment epithelium (RPE) were quantified by qRT-PCR and transcriptomic changes were analyzed by RNA-sequencing. Retinal thickness and structure were evaluated by optical coherence tomography. Results We found that galectin-3 expression was strongly upregulated in reactive retinal mononuclear phagocytes of AMD patients and in the two related mouse models of light-induced retinal degeneration. The experimental in vivo data further showed that specific targeting of galectin-3 by genetic knockout or administration of the small-molecule inhibitor TD139 reduced microglia reactivity and delayed retinal damage in both light damage conditions. Conclusion This study defines galectin-3 as a potent driver of retinal degeneration and highlights the protein as a drug target for ocular immunomodulatory therapies. © The Author(s) 2022 |
| abstract_unstemmed |
Background Dysfunctional humoral and cellular innate immunity are key components in the development and progression of age-related macular degeneration (AMD). Specifically, chronically activated microglia and their disturbed regulatory system contribute to retinal degeneration. Galectin-3, a β-galactose binding protein, is a potent driver of macrophage and microglia activation and has been implicated in neuroinflammation, including neurodegenerative diseases of the brain. Here, we hypothesized that genetic deficiency of galectin-3 or its modulation via TD139 dampens mononuclear phagocyte reactivity and delays retinal degeneration. Methods Galectin-3 expression in AMD patients was analyzed by immunohistochemical stainings. Galectin-3 knockout and BALB/cJ mice were exposed to white bright light with an intensity of 15,000 lux for 1 h and $ Cx3cr1^{GFP/+} $ mice to focal blue light of 50,000 lux for 10 min. BALB/cJ and $ Cx3cr1^{GFP/+} $ mice received intraperitoneal injections of 15 mg/kg TD139 or vehicle for five consecutive days, starting one day prior to light exposure. The effects of galectin-3 deficiency or inhibition on microglia were analyzed by immunohistochemical stainings and in situ hybridization of retinal sections and flat mounts. Pro-inflammatory cytokine levels in the retina and retinal pigment epithelium (RPE) were quantified by qRT-PCR and transcriptomic changes were analyzed by RNA-sequencing. Retinal thickness and structure were evaluated by optical coherence tomography. Results We found that galectin-3 expression was strongly upregulated in reactive retinal mononuclear phagocytes of AMD patients and in the two related mouse models of light-induced retinal degeneration. The experimental in vivo data further showed that specific targeting of galectin-3 by genetic knockout or administration of the small-molecule inhibitor TD139 reduced microglia reactivity and delayed retinal damage in both light damage conditions. Conclusion This study defines galectin-3 as a potent driver of retinal degeneration and highlights the protein as a drug target for ocular immunomodulatory therapies. © The Author(s) 2022 |
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Genetic targeting or pharmacological inhibition of galectin-3 dampens microglia reactivity and delays retinal degeneration |
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Wolf, Anne Szczepan, Manon Xu, Heping Jägle, Herbert Moehle, Christoph Chen, Mei Langmann, Thomas |
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