Toll-like Receptor 3 and Geographic Atrophy in Age-Related Macular Degeneration

Abstract

BACKGROUND Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. Advanced AMD is comprised of geographic atrophy (GA) and choroidal neovascularization (CNV). Specific genetic variants that predispose for GA are largely unknown. METHODS We tested (i) for association between the functional toll-like receptor-3 (TLR3) variant rs3775291 (L412F) and AMD in European Americans and (ii) the effect of TLR3 L and F variants on the viability of human retinal pigment epithelium (RPE) cells in vitro and on RPE cell apoptosis in wildtype and Tlr3−/− mice. RESULTS The F variant (or T allele at single nucleotide polymorphism at rs3775291) was associated with protection against GA (P=0.005); this association was replicated in two independent GA case-control series (P=5.43×10−4 and P=0.002, respectively. We observed no association between TLR3 variants and CNV. The rs377291 variant is probably critical to the function of TLR3, because a prototypic TLR3 ligand induced cell death and apoptosis in human RPE cells with the LL genotype to a greater extent than it did RPE cells with the LF genotype. Moreover, the ligand induced more RPE cell death and apoptosis in wild-type than in Tlr3−/− mice. CONCLUSIONS The TLR3 412F variant confers protection against GA, probably by suppressing RPE cell death. Given that double stranded RNA can activate TLR3-mediated apoptosis, our results suggest a possible role for viral dsRNA transcripts in the development of GA and raise awareness of potential toxicity induced by short interfering RNA (siRNA) therapeutics in the eye.

Toll-like Receptor 3 Is Required for Development of Retinopathy Caused by Impaired All-trans-retinal Clearance in Mice

“…Furthermore, TLR3 stimulation of RPE cells induced the secretion of various cytokines, chemokines, and adhesion molecules. Poly(I-C), a synthetic dsRNA, induced apoptosis via TLR3 in both human and mouse RPE cells (20,21). Thus, TLR3-mediated signaling triggered by dsRNA might play a role in retinal diseases.…”

Genomic organization and expression analysis of Toll-like receptor 3 in grass carp (Ctenopharyngodon idella)

“…Double-stranded RNA is a marker for viral infection that is recognized by TLR3 [2]. TLR3 triggers specific signaling pathways that culminate in the activation of NF-kB and IRF3 transcription factors, as well as apoptosis, enabling the host to mount an effective innate immune response through the induction of cytokines, chemokines, and other proinflammatory mediators [3,4]. The adjuvant role of poly I:C also requires TLR3 [5].…”

Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration

“…Whereas RIP1 acts as a multifunctional adaptor protein that regulates NF-kB-dependent inflammation, apoptosis and necrosis in TLR3 signaling, RIP3 has a more specific role, which induces necrosis through the formation of the pro-necrotic complex. 22,23 Although previous studies have shown that intraocular injection of polyinosinic-polycytidylic acid (poly(I : C)), a synthetic analog of dsRNA, induces TLR3-dependent retinal degeneration, 24,25 the downstream molecular and biological events were not elucidated. In this study, we examined the mechanism of cell death of RPE and photoreceptors in dsRNA-induced retinal degeneration and identified programmed necrosis to promote inflammation by regulating the release of intracellular DAMPs and to be crucial in dsRNA-induced retinal degeneration.…”