cFLIP in the molecular regulation of astroglia-driven neuroinflammation in experimental glaucoma.

Autor: Yang X; Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA., Zeng Q; Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA., İnam MG; Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA., İnam O; Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA., Lin CS; Department of Pathology & Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA., Tezel G; Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA. gt2320@cumc.columbia.edu.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2024 Jun 01; Vol. 21 (1), pp. 145. Date of Electronic Publication: 2024 Jun 01.
DOI: 10.1186/s12974-024-03141-4
Abstrakt: Background: Recent experimental studies of neuroinflammation in glaucoma pointed to cFLIP as a molecular switch for cell fate decisions, mainly regulating cell type-specific caspase-8 functions in cell death and inflammation. This study aimed to determine the importance of cFLIP for regulating astroglia-driven neuroinflammation in experimental glaucoma by analyzing the outcomes of astroglia-targeted transgenic deletion of cFLIP or cFLIP L .
Methods: Glaucoma was modeled by anterior chamber microbead injections to induce ocular hypertension in mouse lines with or without conditional deletion of cFLIP or cFLIP L in astroglia. Morphological analysis of astroglia responses assessed quantitative parameters in retinal whole mounts immunolabeled for GFAP and inflammatory molecules or assayed for TUNEL. The molecular analysis included 36-plexed immunoassays of the retina and optic nerve cytokines and chemokines, NanoString-based profiling of inflammation-related gene expression, and Western blot analysis of selected proteins in freshly isolated samples of astroglia.
Results: Immunoassays and immunolabeling of retina and optic nerve tissues presented reduced production of various proinflammatory cytokines, including TNFα, in GFAP/cFLIP and GFAP/cFLIP L relative to controls at 12 weeks of ocular hypertension with no detectable alteration in TUNEL. Besides presenting a similar trend of the proinflammatory versus anti-inflammatory molecules displayed by immunoassays, NanoString-based molecular profiling detected downregulated NF-κB/RelA and upregulated RelB expression of astroglia in ocular hypertensive samples of GFAP/cFLIP compared to ocular hypertensive controls. Analysis of protein expression also revealed decreased phospho-RelA and increased phospho-RelB in parallel with an increase in caspase-8 cleavage products.
Conclusions: A prominent response limiting neuroinflammation in ocular hypertensive eyes with cFLIP-deletion in astroglia values the role of cFLIP in the molecular regulation of glia-driven neuroinflammation during glaucomatous neurodegeneration. The molecular responses accompanying the lessening of neurodegenerative inflammation also seem to maintain astroglia survival despite increased caspase-8 cleavage with cFLIP deletion. A transcriptional autoregulatory response, dampening RelA but boosting RelB for selective expression of NF-κB target genes, might reinforce cell survival in cFLIP-deleted astroglia.
(© 2024. The Author(s).)
Databáze: MEDLINE
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