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Review
. 2022 Mar 31:2:850394.
doi: 10.3389/fopht.2022.850394. eCollection 2022.

Toll-Like Receptor Signalling Pathways and the Pathogenesis of Retinal Diseases

Owuraku Titi-Lartey  1 , Imran Mohammed  1 , Winfried M Amoaku  1
Affiliations
Review

Toll-Like Receptor Signalling Pathways and the Pathogenesis of Retinal Diseases

Owuraku Titi-Lartey et al. Front Ophthalmol (Lausanne). .

Abstract

There is growing evidence that the pathogenesis of retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD) have a significant chronic inflammatory component. A vital part of the inflammatory cascade is through the activation of pattern recognition receptors (PRR) such as toll-like receptors (TLR). Here, we reviewed the past and current literature to ascertain the cumulative knowledge regarding the effect of TLRs on the development and progression of retinal diseases. There is burgeoning research demonstrating the relationship between TLRs and risk of developing retinal diseases, utilising a range of relevant disease models and a few large clinical investigations. The literature confirms that TLRs are involved in the development and progression of retinal diseases such as DR, AMD, and ischaemic retinopathy. Genetic polymorphisms in TLRs appear to contribute to the risk of developing AMD and DR. However, there are some inconsistencies in the published reports which require further elucidation. The evidence regarding TLR associations in retinal dystrophies including retinitis pigmentosa is limited. Based on the current evidence relating to the role of TLRs, combining anti-VEGF therapies with TLR inhibition may provide a longer-lasting treatment in some retinal vascular diseases.

Keywords: age-related macular degeneration; diabetic retinopathy; genetic polymorphisms; inflammation; ischaemic retinopathy; retinal diseases; retinal dystrophies; toll-like receptors.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Location of TLRs on retinal cells. RPE cells: Human RPE cells express mRNA for TLRs 1-10 excluding TLR8. TLRs 1 and 3 being the most highly expressed at mRNA level. Protein of TLR 2-4, and -9 have also been identified. Choroidal endothelial cell: Human choroidal endothelial cells express mRNA for TLRs 1-6 and 9 and protein for TLRs 2-6 and 9. Retinal endothelial cell: Human retinal endothelial cells express mRNA for TLRs 1-4, -6 and -9 and protein for TLRs 3, 4, 6 and 9 (17). Muller glial cell: Human muller cells express mRNA and protein for TLRs 1-10. Photoreceptors: Photoreceptors from the 661W murine cell line express TLR4 protein.
Figure 2
Figure 2
TLR-3 and TLR-4 signalling pathways [adapted from (34)]. TLR3 receptors are located intracellularly in endosomal compartments whereas TLR4 is located on the cell surface. Activation of the TLRs initiate signalling pathways downstream of two adaptor proteins, TRIF and MyD88. Activation of the TIRAP pathway leads to formation of the myddosome complex which comprises MyD88, IRAK 4 and IRAK1. Activated IRAK1 induces TRAF6 after k63 polyubiquitination, this leads to activation of TAK1 which subsequently activates the IKK complex-NF-κB and MAPK. Activation of the TRAM pathway via the TRIF adaptor leads to the activation of TRAF6 and TRAF3, TRAF6 recruits the RIP1 kinase which activates the TAK1 complex which subsequently triggers the MAPK and NF-κB signalling pathways. The IKK related kinases, IKKI and TBK1, are recruited by TRAF3 and this leads to phosphorylation of IRF3 leading to Type 1 interferon transcription.
Figure 3
Figure 3
Flow chart showing the article selection process.
Figure 4
Figure 4
Schematic representation of TLRs involvement in diabetic retinopathy. Initiation of the pathological endothelial changes seen in diabetes are dependent on TLR-2 and -4. HMGB1 levels are raised in response to hyperglycaemia in rat endothelial cells and the source may be from bone marrow derived cells or from dying endothelial cells. HMGB1 binds to the TLR4 receptor initiating activation of the NF-κB pathway leading to subsequent increased levels of TNF-α and VEGF in RPE cells. Diabetes induced miRNA-499-3p triggers the levels of TLR4 via inhibition of INFA2 leading to reduced endothelial cell proliferation and increased apoptosis. Retinal endothelial cell apoptosis is associated with raised levels of markers of apoptosis such as bax and caspase-3 and reduction of anti-apoptotic markers such as BCL-2. Hyperglycaemic condition exacerbates the levels of TNF-α, NF-κB and VEGF production in ARPE19.
Figure 5
Figure 5
Schematic representation of TLRs involvement in retinal ischaemia. In response to retinal ischaemia, various damage associated molecular patterns (DAMPs) such as HSP70 and HMGB1 induces inflammatory response via the TLR4-MyD88 pathway. HMGB1 binds to TLR4 receptors leading to retinal ganglion cell loss and activation of inflammatory pathways. Retinal ischaemia also elevates the levels of TLR-1 to -3 in retinal ganglion cells leading to pro-inflammatory tissue damage.
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