June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Upregulation of pro-inflammatory genes accompanies photoreceptors demise in canine models of retinal degeneration
Author Affiliations & Notes
  • Tatyana Appelbaum
    Clinical Studies, U of Penn School Vet Med, Philadelphia, Pennsylvania, United States
  • Evelyn Santana
    Clinical Studies, U of Penn School Vet Med, Philadelphia, Pennsylvania, United States
  • Gustavo D Aguirre
    Clinical Studies, U of Penn School Vet Med, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Tatyana Appelbaum, None; Evelyn Santana, None; Gustavo Aguirre, None
  • Footnotes
    Support  EY-06855, -17549, the Foundation Fighting Blindness, the Van Sloun Fund for Canine Genetic Research, and Hope for Vision
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 3587. doi:
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    • Get Citation

      Tatyana Appelbaum, Evelyn Santana, Gustavo D Aguirre; Upregulation of pro-inflammatory genes accompanies photoreceptors demise in canine models of retinal degeneration
      . Invest. Ophthalmol. Vis. Sci. 2017;58(8):3587.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To examine regulation of the immune response in three early-onset canine models of human retinitis pigmentosa (RP): rod cone dysplasia 1 (rcd1), X-linked progressive retinal atrophy 2 (xlpra2), and early retinal degeneration (erd) caused, respectively, by mutations in PDE6B, RPGR-ORF15 (del1084–1085), and STK38L, and the late-onset model, xlpra1, caused by a 5-bp microdeletion (del1028-1032) in RPGR-ORF15.

Methods : Retinal samples from rcd1, xlpra2, erd and xlpra1 affected and control dogs were used for immunohistochemistry (IHC), western blot and gene expression (GE) analysis. qRT-PCR was used to examine the expression of 39 genes. Expression profiles were analyzed at different time points relevant to the onset and progression of the disease.

Results : Analysis of GE data sets identified early activation of immune response genes, including genes encoding constituents of NLRP3 inflammasome, its substrates (pro-IL1B, pro-IL18), and common components of IL1B, IL18 and TLR4 pathways in rcd1, xlpra2 and erd. In early-onset models, gradual increase in the number of upregulated pro-inflammatory genes and extent of GE upregulation, was most prominent in rcd1 and consistent with disease progression and severity. In late-onset xlpra1 retinas, a subset of the pro-inflammatory genes was highly upregulated long before any disease-related morphological changes. Notably, strong upregulation of the immune response genes was not always followed by overexpression of their proteins. Double labeling with PYCARD and CD18 identified microglia and infiltrating macrophages as a source of the inflammasome in the mutant retinas. Of the two activated caspase 1 cleavage products, IL1B and IL18, only IL1B was detected in rcd1 and xlpra2 thus highlighting the role of this pathway in the disease progression, while precursor IL18 remained unprocessed in the same protein extract. Of IL4, MANF, CX3CL1 and TGFB, known for moderating immune response, IL4 was highly upregulated in late-onset xlpra1; IL4 and CX3CL1 were slightly upregulated in rcd1, and none were elevated in xlpra1 and erd models.

Conclusions : Expression data indicate an upregulated immune response accompanying the progression of retinal degeneration in animal models of human RP thus pointing out to potential benefits of anti-inflammatory therapy.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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