IOP induces upregulation of GFAP and MHC-II and microglia reactivity in mice retina contralateral to experimental glaucoma
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BACKGROUND: Ocular hypertension is a major risk factor for glaucoma, a neurodegenerative disease characterized by an irreversible decrease in ganglion cells and their axons. Macroglial and microglial cells appear to play an important role in the pathogenic mechanisms of the disease. Here, we study the effects of laser-induced ocular hypertension (OHT) in the macroglia, microglia and retinal ganglion cells (RGCs) of eyes with OHT (OHT-eyes) and contralateral eyes two weeks after lasering. METHODS: Two groups of adult Swiss mice were used: age-matched control (naïve, n=9); and lasered (n=9). In the lasered animals, both OHT-eyes and contralateral eyes were analyzed. Retinal whole-mounts were immunostained with antibodies against glial fibrillary acid protein (GFAP), neurofilament of 200 kD (NF-200), ionized calcium binding adaptor molecule (Iba-1) and major histocompatibility complex class II molecule (MHC-II). The GFAP-labeled retinal area (GFAP-RA), the intensity of GFAP immunoreaction (GFAP-IR), and the number of astrocytes and NF-200 + RGCs were quantified. RESULTS: In comparison with naïve: i) astrocytes were more robust in contralateral eyes. In OHT-eyes, the astrocyte population was not homogeneous, given that astrocytes displaying only primary processes coexisted with astrocytes in which primary and secondary processes could be recognized, the former having less intense GFAP-IR (P<0.001); ii) GFAP-RA was increased in contralateral (P<.05) and decreased in OHT-eyes (P <0.001); iii) the mean intensity of GFAP-IR was higher in OHT-eyes (P<0.01), and the percentage of the retinal area occupied by GFAP+ cells with higher intensity levels was increased in contralateral (P=0.05) and in OHT-eyes (P<0.01); iv) both in contralateral and in OHT-eyes, GFAP was upregulated in Müller cells and microglia was activated; v) MHC-II was upregulated on macroglia and microglia. In microglia, it was similarly expressed in contralateral and OHT-eyes. By contrast, in macroglia, MHC-II upregulation was observed mainly in astrocytes in contralateral eyes and in Müller cells in OHT-eyes; vi) NF-200+ RGCs (degenerated cells) appeared in OHT-eyes with a trend for the GFAP-RA to decrease and for the NF-200+RGC number to increase from the center to the periphery (r= -0.45). CONCLUSION: The use of the contralateral eye as an internal control in experimental induction of unilateral IOP should be reconsidered. The gliotic behavior in contralateral eyes could be related to the immune response. The absence of NF-200+RGCs (sign of RGC degeneration) leads us to postulate that the MHC-II upregulation in contralateral eyes could favor neuroprotection.
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These glaucoma-related alterations can lead to secondary damage such as excitotoxicity, neurotrophin deprivation, oxidative damage, mitochondrial dysfunction, and eventually retinal ganglion cell death.
“These alterations can lead to secondary damage such as, excitotoxicity, neurotrophin deprivation, oxidative damage, mitochondrial dysfunction, and eventually RGC death (Nickells, 1999; Gallego et al., 2012).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Gallego et al., 2012
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Macro- and microglial responses in the fellow eyes contralateral to glaucomatous eyes
Ramirez, A. I., Salazar, J. J., de Hoz, R., Rojas, B., Gallego, B., Salobrar‐García, E., Valiente‐Soriano, F. J., Triviño, A., & Ramirez, J. M. (2015) · Progress in brain research · doi:10.1016/bs.pbr.2015.05.003 · Cited by 31 · see citing works
Self-citationLow-dose minocycline mediated neuroprotection on retinal ischemia-reperfusion injury of mice.
Huang, R., Liang, S., Fang, L., Wu, M., Cheng, H., Mi, X.-S., & Ding, Y. (2018) · PubMed Central · Cited by 31 · see citing works
Immunomodulation as a Neuroprotective Strategy for Glaucoma Treatment
Barış, M. E., & Tezel, G. (2019) · Current Ophthalmology Reports · doi:10.1007/s40135-019-00212-1 · Cited by 31 · see citing works
Means, J. C., Lopez, A. A., & Koulen, P. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-019-00781-6 · Cited by 32 · see citing works
Graphene glial-interfaces: challenges and perspectives
Fabbri, R., Saracino, E., Treossi, E., Zamboni, R., Palermo, V., & Benfenati, V. (2021) · Nanoscale · doi:10.1039/d0nr07824g · Cited by 31 · see citing works
Pierdomenico, J. D., García‐Ayuso, D., Jiménez-López, M., Agudo‐Barriuso, M., Vidal‐Sanz, M., & Villegas‐Pérez, M. P. (2016) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.16-19618 · Cited by 31 · see citing works
Self-citation
- Authors
- Gallego, B. I., Salazar, J. J., de Hoz, R., Rojas, B., Ramírez, A. I., Salinas-Navarro, M., Ortín-Martínez, A., Valiente-Soriano, F. J., Avilés-Trigueros, M., Villegas-Perez, M. P., Vidal-Sanz, M., Triviño, A., & Ramírez, J. M.
- Affiliations
- Universidad Complutense de Madrid (ES)
- Universidad de Murcia (ES)
- Venue
- Journal of Neuroinflammation
- Published
- 2012-05-14
- Volume
- 9
- Issue
- 1
- Pages
- 92-92
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC3410794
- OpenAlex
- W2029522517
- Cited by
- 224
- References
- 88
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 5 · 2023: 17 · 2022: 18 · 2021: 29 · 2020: 22 · 2019: 15 · 2018: 10 · 2017: 21 · 2016: 24 · 2015: 22 · 2014: 15 · 2013: 8 · 2012: 4
- FWCI
- 14.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
- Library Open Repository (Universidad Complutense Madrid) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fundación Mutua Madrileña (4131173)
- Universidad Complutense de Madrid (GR35/10A, GR35/10)
- Ministerio de Ciencia e Innovación
- Instituto de Salud Carlos III (RD07/0062/0000, RD07/0062)
- Topics
- Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- experimental glaucoma, ocular hypertension, laser-induced ocular hypertension, microglial activation, astrocytes, glial fibrillary acidic protein, MHC class II, retinal ganglion cells, Müller cells, neuroinflammation, fellow eye, neurodegeneration, neurofilaments, Iba1, mice, glaucoma risk factors, neuroprotection
- MeSH terms
- Animals, Histocompatibility Antigens Class II, Astrocytes, Cell Count, Glaucoma, Glial Fibrillary Acidic Protein, Intraocular Pressure, Male, Nerve Tissue Proteins, Ocular Hypertension, Retina, Retinal Ganglion Cells, Up-Regulation, Microglia, Mice
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