Retinal response to systemic inflammation differs between sexes and neurons
BackgroundNeurological dysfunction and glial activation are common in severe infections such as sepsis. There is a sexual dimorphism in the response to systemic inflammation in both patients and animal models, but there are few comparative studies. Here, we investigate the effect of systemic inflamm...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1340013/full |
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| author | Kristy T. Rodríguez-Ramírez María Norte-Muñoz Fernando Lucas-Ruiz Alejandro Gallego-Ortega Francesco Calzaferri David García-Bernal Carlos M. Martínez Caridad Galindo-Romero Cristóbal de los Ríos Cristóbal de los Ríos Manuel Vidal-Sanz Marta Agudo-Barriuso |
| author_facet | Kristy T. Rodríguez-Ramírez María Norte-Muñoz Fernando Lucas-Ruiz Alejandro Gallego-Ortega Francesco Calzaferri David García-Bernal Carlos M. Martínez Caridad Galindo-Romero Cristóbal de los Ríos Cristóbal de los Ríos Manuel Vidal-Sanz Marta Agudo-Barriuso |
| author_sort | Kristy T. Rodríguez-Ramírez |
| collection | DOAJ |
| description | BackgroundNeurological dysfunction and glial activation are common in severe infections such as sepsis. There is a sexual dimorphism in the response to systemic inflammation in both patients and animal models, but there are few comparative studies. Here, we investigate the effect of systemic inflammation induced by intraperitoneal administration of lipopolysaccharide (LPS) on the retina of male and female mice and determine whether antagonism of the NLRP3 inflammasome and the extrinsic pathway of apoptosis have protective effects on the retina.MethodsA single intraperitoneal injection of LPS (5 mg/kg) was administered to two months old C57BL/6J male and female mice. Retinas were examined longitudinally in vivo using electroretinography and spectral domain optical coherence tomography. Retinal ganglion cell (RGC) survival and microglial activation were analysed in flat-mounts. Retinal extracts were used for flow cytometric analysis of CD45 and CD11b positive cells. Matched plasma and retinal levels of proinflammatory cytokines were measured by ELISA. Retinal function and RGC survival were assessed in animals treated with P2X7R and TNFR1 antagonists alone or in combination.ResultsIn LPS-treated animals of both sexes, there was transient retinal dysfunction, loss of vision-forming but not non-vision forming RGCs, retinal swelling, microglial activation, cell infiltration, and increases in TNF and IL-1β. Compared to females, males showed higher vision-forming RGC death, slower functional recovery, and overexpression of lymphotoxin alpha in their retinas. P2X7R and TNFR1 antagonism, alone or in combination, rescued vision-forming RGCs. P2X7R antagonism also rescued retinal function. Response to treatment was better in females than in males.ConclusionsSystemic LPS has neuronal and sex-specific adverse effects in the mouse retina, which are counteracted by targeting the NLRP3 inflammasome and the extrinsic pathway of apoptosis. Our results highlight the need to analyse males and females in preclinical studies of inflammatory diseases affecting the central nervous system |
| first_indexed | 2024-03-08T05:02:21Z |
| format | Article |
| id | doaj.art-5bea71dc8bc24dea91e20bde40d942b6 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-08T05:02:21Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5bea71dc8bc24dea91e20bde40d942b62024-02-07T10:52:29ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-02-011510.3389/fimmu.2024.13400131340013Retinal response to systemic inflammation differs between sexes and neuronsKristy T. Rodríguez-Ramírez0María Norte-Muñoz1Fernando Lucas-Ruiz2Alejandro Gallego-Ortega3Francesco Calzaferri4David García-Bernal5Carlos M. Martínez6Caridad Galindo-Romero7Cristóbal de los Ríos8Cristóbal de los Ríos9Manuel Vidal-Sanz10Marta Agudo-Barriuso11Grupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, SpainGrupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, SpainGrupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, SpainGrupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, SpainInstituto-Fundación Teófilo Hernando and Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, SpainGrupo de Trasplante Hematopoyético y Terapia Celular, Departamento de Bioquímica y Biología Molecular B e Inmunología, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, SpainPlataforma de Patología, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, SpainGrupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, SpainInstituto-Fundación Teófilo Hernando and Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, SpainDepartamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, SpainGrupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, SpainGrupo de Investigación Oftalmología Experimental, Departamento de Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica, Facultad de Medicina, Universidad de Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, SpainBackgroundNeurological dysfunction and glial activation are common in severe infections such as sepsis. There is a sexual dimorphism in the response to systemic inflammation in both patients and animal models, but there are few comparative studies. Here, we investigate the effect of systemic inflammation induced by intraperitoneal administration of lipopolysaccharide (LPS) on the retina of male and female mice and determine whether antagonism of the NLRP3 inflammasome and the extrinsic pathway of apoptosis have protective effects on the retina.MethodsA single intraperitoneal injection of LPS (5 mg/kg) was administered to two months old C57BL/6J male and female mice. Retinas were examined longitudinally in vivo using electroretinography and spectral domain optical coherence tomography. Retinal ganglion cell (RGC) survival and microglial activation were analysed in flat-mounts. Retinal extracts were used for flow cytometric analysis of CD45 and CD11b positive cells. Matched plasma and retinal levels of proinflammatory cytokines were measured by ELISA. Retinal function and RGC survival were assessed in animals treated with P2X7R and TNFR1 antagonists alone or in combination.ResultsIn LPS-treated animals of both sexes, there was transient retinal dysfunction, loss of vision-forming but not non-vision forming RGCs, retinal swelling, microglial activation, cell infiltration, and increases in TNF and IL-1β. Compared to females, males showed higher vision-forming RGC death, slower functional recovery, and overexpression of lymphotoxin alpha in their retinas. P2X7R and TNFR1 antagonism, alone or in combination, rescued vision-forming RGCs. P2X7R antagonism also rescued retinal function. Response to treatment was better in females than in males.ConclusionsSystemic LPS has neuronal and sex-specific adverse effects in the mouse retina, which are counteracted by targeting the NLRP3 inflammasome and the extrinsic pathway of apoptosis. Our results highlight the need to analyse males and females in preclinical studies of inflammatory diseases affecting the central nervous systemhttps://www.frontiersin.org/articles/10.3389/fimmu.2024.1340013/fullmalefemalelipopolysaccharideinflammationcentral nervous systemneuronal death |
| spellingShingle | Kristy T. Rodríguez-Ramírez María Norte-Muñoz Fernando Lucas-Ruiz Alejandro Gallego-Ortega Francesco Calzaferri David García-Bernal Carlos M. Martínez Caridad Galindo-Romero Cristóbal de los Ríos Cristóbal de los Ríos Manuel Vidal-Sanz Marta Agudo-Barriuso Retinal response to systemic inflammation differs between sexes and neurons Frontiers in Immunology male female lipopolysaccharide inflammation central nervous system neuronal death |
| title | Retinal response to systemic inflammation differs between sexes and neurons |
| title_full | Retinal response to systemic inflammation differs between sexes and neurons |
| title_fullStr | Retinal response to systemic inflammation differs between sexes and neurons |
| title_full_unstemmed | Retinal response to systemic inflammation differs between sexes and neurons |
| title_short | Retinal response to systemic inflammation differs between sexes and neurons |
| title_sort | retinal response to systemic inflammation differs between sexes and neurons |
| topic | male female lipopolysaccharide inflammation central nervous system neuronal death |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1340013/full |
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