Lysyl oxidase like-1 deficiency in optic nerve head astrocytes elicits reactive astrocytosis and alters functional effects of astrocyte derived exosomes.

Autor: Hariani HN; Graduate Program in Neuroscience, Loyola University Chicago, Maywood, IL, 60153, USA; Research Service, Edward Hines Jr Veterans Affairs Hospital, Hines, IL, 60141, USA., Ghosh AK; Graduate Program in Neuroscience, Loyola University Chicago, Maywood, IL, 60153, USA; Research Service, Edward Hines Jr Veterans Affairs Hospital, Hines, IL, 60141, USA., Rosen SM; Department of Ophthalmology, Loyola University Chicago, Maywood, IL, 60153, USA; Department of Radiology, UC Davis Medical Center, Sacramento, CA, 95817, USA., Tso HY; Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Kessinger C; Graduate Program in Neuroscience, Loyola University Chicago, Maywood, IL, 60153, USA., Zhang C; Graduate Program in Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL, 60153, USA., Jones WK; Department of Molecular Pharmacology and Neuroscience, Loyola University Chicago, Maywood, IL, 60153, USA., Sappington RM; Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, 27109, USA; Translational Eye and Vision Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, 27109, USA., Mitchell CH; Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Stubbs EB Jr; Department of Ophthalmology, Loyola University Chicago, Maywood, IL, 60153, USA; Research Service, Edward Hines Jr Veterans Affairs Hospital, Hines, IL, 60141, USA., Rao VR; Department of Ophthalmology, Loyola University Chicago, Maywood, IL, 60153, USA; Research Service, Edward Hines Jr Veterans Affairs Hospital, Hines, IL, 60141, USA., Kaja S; Department of Ophthalmology, Loyola University Chicago, Maywood, IL, 60153, USA; Department of Molecular Pharmacology and Neuroscience, Loyola University Chicago, Maywood, IL, 60153, USA; Research Service, Edward Hines Jr Veterans Affairs Hospital, Hines, IL, 60141, USA. Electronic address: skaja@luc.edu.
Jazyk: angličtina
Zdroj: Experimental eye research [Exp Eye Res] 2024 Mar; Vol. 240, pp. 109813. Date of Electronic Publication: 2024 Feb 06.
DOI: 10.1016/j.exer.2024.109813
Abstrakt: Glaucoma is a multifactorial progressive ocular pathology that manifests clinically with damage to the optic nerve (ON) and the retina, ultimately leading to blindness. The optic nerve head (ONH) shows the earliest signs of glaucoma pathology, and therefore, is an attractive target for drug discovery. The goal of this study was to elucidate the effects of reactive astrocytosis on the elastin metabolism pathway in primary rat optic nerve head astrocytes (ONHA), the primary glial cell type in the unmyelinated ONH. Following exposure to static equibiaxial mechanical strain, we observed prototypic molecular and biochemical signatures of reactive astrocytosis that were associated with a decrease in lysyl oxidase like 1 (Loxl1) expression and a concomitant decrease in elastin (Eln) gene expression. We subsequently investigated the role of Loxl1 in reactive astrocytosis by generating primary rat ONHA cultures with ∼50% decreased Loxl1 expression. Our results suggest that reduced Loxl1 expression is sufficient to elicit molecular signatures of elastinopathy in ONHA. Astrocyte derived exosomes (ADE) significantly increased the length of primary neurites of primary neurons in vitro. In contrast, ADE from Loxl1-deficient ONHA were deficient of trophic effects on neurite outgrowth in vitro, positing that Loxl1 dysfunction and the ensuing impaired elastin synthesis during reactive astrocytosis in the ONH may contribute to impaired neuron-glia signaling in glaucoma. Our data support a role of dysregulated Loxl1 function in eliciting reactive astrocytosis in glaucoma subtypes associated with increased IOP, even in the absence of genetic polymorphisms in LOXL1 typically associated with exfoliation glaucoma. This suggests the need for a paradigm shift toward considering lysyl oxidase activity and elastin metabolism and signaling as contributors to an altered secretome of the ONH that may lead to the progression of glaucomatous changes. Future research is needed to investigate cargo of exosomes in the context of reactive astrocytosis and identify the pathways leading to the observed transcriptome changes during reactive astrocytosis.
(Published by Elsevier Ltd.)
Databáze: MEDLINE
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