Retinal Pigment Epithelium Expressed Toll-like Receptors and Their Potential Role in Age-Related Macular Degeneration

Abstract

(1) Background: Inflammation is a major pathomechanism in the development and progression of age-related macular degeneration (AMD). The retinal pigment epithelium (RPE) may contribute to retinal inflammation via activation of its Toll-like receptors (TLR). TLR are pattern recognition receptors that detect the pathogen- or danger-associated molecular pattern. The involvement of TLR activation in AMD is so far not understood. (2) Methods: We performed a systematic literature research, consulting the National Library of Medicine (PubMed). (3) Results: We identified 106 studies, of which 54 were included in this review. Based on these studies, the current status of TLR in AMD, the effects of TLR in RPE activation and of the interaction of TLR activated RPE with monocytic cells are given, and the potential of TLR activation in RPE as part of the AMD development is discussed. (4) Conclusion: The activation of TLR2, -3, and -4 induces a profound pro-inflammatory response in the RPE that may contribute to (long-term) inflammation by induction of pro-inflammatory cytokines, reducing RPE function and causing RPE cell degeneration, thereby potentially constantly providing new TLR ligands, which could perpetuate and, in the long run, exacerbate the inflammatory response, which may contribute to AMD development. Furthermore, the combined activation of RPE and microglia may exacerbate neurotoxic effects.

Microbiota mitochondria disorders as hubs for early age-related macular degeneration

“…The activation of TLR2-3-4 induces pro-inflammatory responses in the RPE that may contribute to low-grade inflammation, modifying RPE functions and contributing to RPE degeneration [ 250 ]. In contrast, TLR9 recognizes viral or bacterial DNA with unmethylated CpG motifs, which decreases inflammation and enhances phagocytosis in RPE cells [ 251 ]. The protective effect of CpG oligodinucleotide in the mitigation of apoptosis is dependent on the reduction of ROS [ 252 ].…”

The complement C3a‑C3aR and C5a‑C5aR pathways promote viability and inflammation of human retinal pigment epithelium cells by targeting NF‑κB signaling

“…HRPE cells were divided into six groups and treated as follows. In the first group, HRPE cells (3x10 3 or 3x10 5 per well) were subjected to 0.5, 1, 2, 4 and 8 µg/ml of recombinant endotoxin-free human complement component C3a protein (R&D Systems, Inc) for 24 or 48 h. In the second group, HRPE cells (3x10 3 or 3x10 5 per well) were exposed to 0.5, 1, 2, 4 and 8 µg/ml of recombinant endotoxin-free human complement component C5a protein (R&D Systems, Inc.) for 24 or 48 h (26). In the third group, HRPE cells (3x10 5 per well) were treated with recombinant human complement component C3a protein (2 µg/ml) and NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC; 10 µM; MilliporeSigma) for 24 h. In the fourth group, HRPE cells (3x10 5 per well) received treatment of recombinant human complement component C5a protein (1 µg/ml) and PDTC (10 µM) for 24 h. In the fifth group, HRPE cells (3x10 5 per well) were treated with recombinant human complement component C3a protein (2 µg/ml) and C3aR antagonist SB290157 (20 µM; MilliporeSigma) for 24 h. In the sixth group, HRPE cells (3x10 5 per well) were treated with recombinant human complement component C5a protein (1 µg/ml) and C5aR antagonist CCX168 (2 µM; Abmole Bioscience, Inc.) for 24 h.…”

“…Debilitating eye diseases, such as age-related macular degeneration, retinal detachment (RD) and rhegmatogenous RD associated with choroidal detachment (RRDCD), represent a series of visual health issues that impact the quality of life of affected patients (1)(2)(3). While the etiology and pathogenesis of these disorders remain to be fully elucidated, retinal pigment epithelium (RPE) loss and dysfunction appear to be significant contributors (4)(5)(6). Understanding the underlying mechanisms of phenotypic alterations, including cell viability and inflammation in RPE, should greatly assist the therapy of eye diseases (6)(7)(8).…”

Properties of Cephalopod Skin Ommochromes to Inhibit Free Radicals, and the Maillard Reaction and Retino-Protective Mechanisms in Cellular Models Concerning Oxidative Stress, Angiogenesis, and Inflammation

“…Chronic inflammation that persists due to constant degenerative and pro-inflammatory stimuli is considered a major factor in AMD development [ 22 , 30 ]. The RPE expresses toll-like receptors (TLR) to detect danger-associated molecular patterns and can react to these signals by secreting pro-inflammatory cytokines, which has also been implied to be contributing to the AMD development [ 37 , 38 ]. Among the cytokines that are increased by pro-inflammatory signaling are interleukin 6 (IL-6) and interleukin 8 (IL-8) [ 37 , 39 ].…”