Journal article
Toll-like Receptor 2 Facilitates Oxidative Damage-Induced Retinal Degeneration
Cell reports (Cambridge), Vol.30(7), pp.2209-2224.e5
02/18/2020
DOI: 10.1016/j.celrep.2020.01.064
PMCID: PMC7179253
PMID: 32075760
Abstract
Retinal degeneration is a form of neurodegenerative disease and is the leading cause of vision loss globally. The Toll-like receptors (TLRs) are primary components of the innate immune system involved in signal transduction. Here we show that TLR2 induces complement factors C3 and CFB, the common and rate-limiting factors of the alternative pathway in both retinal pigment epithelial (RPE) cells and mononuclear phagocytes. Neutralization of TLR2 reduces opsonizing fragments of C3 in the outer retina and protects photoreceptor neurons from oxidative stress-induced degeneration. TLR2 deficiency also preserves tight junction expression and promotes RPE resistance to fragmentation. Finally, oxidative stress-induced formation of the terminal complement membrane attack complex and Iba1+ cell infiltration are strikingly inhibited in the TLR2-deficient retina. Our data directly implicate TLR2 as a mediator of retinal degeneration in response to oxidative stress and present TLR2 as a bridge between oxidative damage and complement-mediated retinal pathology.
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•TLR2 activates the alternative complement pathway•TLR2 signaling triggers sub-lytic MAC formation on retinal pigment epithelial cells•TLR2 deficiency reduces oxidative stress-induced C3 and MAC in the outer retina•TLR2 blockade protects photoreceptors and RPE from oxidative stress-induced cell death
Oxidative stress and complement deposition are common to many retinal degenerative diseases. Mulfaul et al. demonstrate that TLR2 blockade protects against photoreceptor neuronal cell death and RPE fragmentation in experimental models of oxidative stress-induced retinal degeneration and present TLR2 as a bridge between oxidative damage and complement-mediated retinal pathology.
Details
- Title: Subtitle
- Toll-like Receptor 2 Facilitates Oxidative Damage-Induced Retinal Degeneration
- Creators
- Kelly Mulfaul - Trinity College DublinEma Ozaki - Trinity College DublinNilisha Fernando - Australian National UniversityKiva Brennan - Trinity College DublinKathleen R Chirco - University of IowaEmma Connolly - Trinity College DublinChris Greene - Trinity College DublinArvydas Maminishkis - National Institutes of HealthRobert G Salomon - Case Western Reserve UniversityMikhail Linetsky - Case Western Reserve UniversityRiccardo Natoli - Australian National UniversityRobert F Mullins - University of IowaMatthew Campbell - Trinity College DublinSarah L Doyle - Trinity College Dublin
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.30(7), pp.2209-2224.e5
- DOI
- 10.1016/j.celrep.2020.01.064
- PMID
- 32075760
- PMCID
- PMC7179253
- NLM abbreviation
- Cell Rep
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: R01EY016813; DOI: 10.13039/100006312, name: BrightFocus Foundation, award: M2016030; DOI: 10.13039/501100001590, name: Health Research Board, award: HRB-HRA/2013.290; DOI: 10.13039/501100001602, name: Science Foundation Ireland, award: SFI 15/CDA/3497; DOI: 10.13039/501100002081, name: Irish Research Council, award: IRCLA/2017/295; DOI: 10.13039/501100021528, name: Royal Victorian Eye and Ear Hospital
- Language
- English
- Date published
- 02/18/2020
- Academic Unit
- The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
- Record Identifier
- 9984182978302771
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