Therapeutic Delivery of Soluble Fractalkine Ameliorates Vascular Dysfunction in the Diabetic Retina
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Published:2024-01-31
Issue:3
Volume:25
Page:1727
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Rodriguez Derek1ORCID, Church Kaira A.1ORCID, Smith Chelsea T.1ORCID, Vanegas Difernando1, Cardona Sandra M.1, Muzzio Isabel A.2ORCID, Nash Kevin R.3ORCID, Cardona Astrid E.1
Affiliation:
1. Department of Molecular Microbiology and Immunology, The University of Texas at San Antonio, San Antonio, TX 78249, USA 2. Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA 52242, USA 3. Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33612, USA
Abstract
Diabetic retinopathy (DR)-associated vision loss is a devastating disease affecting the working-age population. Retinal pathology is due to leakage of serum components into retinal tissues, activation of resident phagocytes (microglia), and vascular and neuronal damage. While short-term interventions are available, they do not revert visual function or halt disease progression. The impact of microglial inflammatory responses on the neurovascular unit remains unknown. In this study, we characterized microglia–vascular interactions in an experimental model of DR. Early diabetes presents activated retinal microglia, vascular permeability, and vascular abnormalities coupled with vascular tortuosity and diminished astrocyte and endothelial cell-associated tight-junction (TJ) and gap-junction (GJ) proteins. Microglia exclusively bind to the neuronal-derived chemokine fractalkine (FKN) via the CX3CR1 receptor to ameliorate microglial activation. Using neuron-specific recombinant adeno-associated viruses (rAAVs), we therapeutically overexpressed soluble (sFKN) or membrane-bound (mFKN) FKN using intra-vitreal delivery at the onset of diabetes. This study highlights the neuroprotective role of rAAV-sFKN, reducing microglial activation, vascular tortuosity, fibrin(ogen) deposition, and astrogliosis and supporting the maintenance of the GJ connexin-43 (Cx43) and TJ zonula occludens-1 (ZO-1) molecules. The results also show that microglia–vascular interactions influence the vascular width upon administration of rAAV-sFKN and rAAV-mFKN. Administration of rAAV-sFKN improved visual function without affecting peripheral immune responses. These findings suggest that overexpression of rAAV-sFKN can mitigate vascular abnormalities by promoting glia–neural signaling. sFKN gene therapy is a promising translational approach to reverse vision loss driven by vascular dysfunction.
Funder
NIH NIH Research Supplement to Promote Diversity in Health-Related Research Program
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference53 articles.
1. Prevalence of Diabetic Retinopathy in the US in 2021;Lundeen;JAMA Ophthalmol.,2023 2. Diabetic retinopathy;Antonetti;N. Engl. J. Med.,2012 3. Current understanding of the molecular and cellular pathology of diabetic retinopathy;Antonetti;Nat. Rev. Endocrinol.,2021 4. Mills, S.A., Jobling, A.I., Dixon, M.A., Bui, B.V., Vessey, K.A., Phipps, J.A., Greferath, U., Venables, G., Wong, V.H.Y., and Wong, C.H.Y. (2021). Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy. Proc. Natl. Acad. Sci. USA, 118. 5. AAV-BR1 targets endothelial cells in the retina to reveal their morphological diversity and to deliver Cx43;Ivanova;J. Comp. Neurol.,2022
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