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Autoimmune-Mediated Retinopathy in CXCR5-Deficient Mice as the Result of Age-Related Macular Degeneration Associated Proteins Accumulation
Univ Missouri, MO 65211 USA; Johns Hopkins Univ, MD 21218 USA.
Univ Missouri, MO 65211 USA; Johns Hopkins Univ, MD 21218 USA.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Cent S Univ, Peoples R China.
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1903Article in journal (Refereed) Published
Abstract [en]

Previous research has shown that CXCR5(-/-) mice develop retinal degeneration (RD) with age, a characteristic related to age macular degeneration (AMD). RD in these mice is not well-understood, and in this study, we sought to characterize further the RD phenotype and to gain mechanistic insights into the function of CXCR5 in the retina. CXCR5(-/-) and WT control mice were used. Fundus images demonstrated a significant (p amp;lt; 0.001) increase of hypo-pigmented spots in the retina of aged CXCR5(-/-) mice compared with WT control mice. PAS staining indicated localization of deposits in the sub-retinal pigment epithelia (RPE) layer. AMD-associated proteins Cryab, amyloid beta, and C3d were detected within the RPE/sub-RPE tissues by immunofluorescence (IF). In addition, western blot analysis of COX-2, Arg1, and VEGF-a revealed an increase in the signaling of these molecules within the RPE/choroid complex. Transmission electron microscopy (TEM) indicated a drusen-like structure of sub-RPE deposits with an accumulation of vacuolated cellular debris. Loss of photoreceptors was detected by peanut lectin staining and was corroborated by a reduction in MAP2 signaling. Loss of blood-retinal barrier integrity was demonstrated by a reduction of ZO-1 expression. Inflammatory cells were detected in the sub-RPE space, with an increase in IBA-1 positive microglia cells on the surface of the RPE. Mass spectrometry analysis of CXCR5(-/-) mouse RPE/choroid proteins extracts, separated by SDS-page and incubated with autologous serum, identified autoantibodies against AMD-associated proteins: Cryaa, Cryab, and Anxa2. In vitro evaluations in BV-2 cell culture indicated a significant increase in production of Arg-1 (p amp;lt; 0.001) and COX-2 (p amp;lt; 0.01) in the presence of anti-CXCR5 antibody when compared with Igg-treated control BV-2 cells stimulated with IL-4 and TNF alpha/IFN gamma, respectively. Anti-CXCR5 antibody treatment without stimulating agents did not affect Arg-1 and COX-2 expression; this suggests that CXCR5 may have a regulatory role in microglia cells activation. These results indicate that with age, CXCR5(-/-) mice develop RD characterized by microglia dysfunction, increased production of CXCL13 in the RPE progressive photoreceptor, neuronal loss, and sub-RPE deposition of cellular debris, resulting in the production of immunogenic proteins and autoimmune-mediated RD.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA , 2019. Vol. 10, article id 1903
Keywords [en]
age macular degeneration; AMD; CXCR5; CXCL13; autoantibody; CRYAA; CRYAB; amyloid beta
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-160041DOI: 10.3389/fimmu.2019.01903ISI: 000480718300001PubMedID: 31474986OAI: oai:DiVA.org:liu-160041DiVA, id: diva2:1349067
Note

Funding Agencies|BrightFocus Foundation [M2014124]; Missouri University start-up fund (Hu Huang research group); NSFC fund [81870677]

Available from: 2019-09-06 Created: 2019-09-06 Last updated: 2019-11-26

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