Toll-Like Receptor 3 Activation Initiates Photoreceptor Cell Death In Vivo and In Vitro

Abstract

PURPOSE. Accumulating evidence has demonstrated that excessive immunoreaction plays a prominent role in the pathogenesis of dry AMD. Toll-like receptor 3 (TLR3) can be activated by double-stranded (ds)RNA in retinal pigment epithelia and trigger an innate immunitymediated inflammatory response. However, its role in photoreceptor cells, the effectors of AMD geographic atrophy, remains unclear.METHODS. The expression of TLR3 was examined in mouse retina and in a murine photoreceptor cell line (661W). Retinal structure, function, and cell death in the polyinosinepolycytidylic acid (poly I:C)-treated retina were investigated by optical coherence tomography, electroretinography (ERG), and immunostaining. Cytokine and chemokine expression as well as cell death were measured in poly I:C-exposed 661W cells and explant retinas. By comparing the RNA sequencing (seq) data of 661W cells and murine retina, we comprehensively investigated the contribution of photoreceptor in poly I:C-induced retinal immune response.RESULTS. Toll-like receptor 3 was highly expressed in the inner segment of the photoreceptor and in 661W cells. We found poly I:C induced significant retinal structural damages and impairment of ERG responses. Focal ERG demonstrated that injected and parainjected zones were functionally damaged by poly I:C. In addition, poly I:C acted on cultured photoreceptor cells directly and evoked an inflammatory response that exhibited similarities with the immune response in mouse retina. Moreover, TLR3 activation initiated cell death in murine photoreceptor cells in vivo and in vitro. Additionally, poly I:C initiated immune response in explant retinas. CONCLUSIONS.We deciphered the TLR3-mediated inflammatory response in photoreceptor cells. Our findings suggested TLR3-mediated inflammatory response in photoreceptor cells may play an important role in dry AMD, offering new insights of potential treatments targeting photoreceptor immunity.

Immunomodulation with minocycline rescues retinal degeneration in juvenile neuronal ceroid lipofuscinosis mice highly susceptible to light damage

“…Of particular interest were those genes that were upregulated in light-triggered Cln3 Δex7/8 animals compared to light-damaged wild-type mice and in turn downregulated with minocycline treatment. Irf7 and Zbp1 , two genes that regulate immune responses and are associated with neuronal cell loss, are highly upregulated in CLN3-deficient and light-triggered mice, and are examples for a possible overshooting immune reaction already described for CLN3-deficient primary microglia ( DeFilippis et al, 2010 ; Gao et al, 2017 ; Mustafi et al, 2012 ; Xiong and Kielian, 2013 ).…”

Protective Effects of Lycium barbarum Extracts on UVB‐Induced Damage in Human Retinal Pigment Epithelial Cells Accompanied by Attenuating ROS and DNA Damage

“…Controversially, the activation of TLR might also create a degenerative effect in neuron cells; for example, Chintala et al's work showed that poly(I:C)-induced TLR3 activation upregulated the protein level of MAPK JNK3 and promoted the degeneration of RGCs in mouse eye [ 61 ]. Similarly, Gao et al's work showed that poly(I:C)-induced TLR3 evoked an inflammatory response and cell death both in murine photoreceptor 661W cells and an in vivo model [ 62 ]. Therefore, the role of TLR in prosurvival or pro-cell death of neuron cells may depend on the types [ 55 ] of stimuli, the level [ 60 ] of stimuli, and the downstream of TLR signaling [ 58 ].…”

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“…The 661W cells were cultured in Dulbecco's modified Eagle's medium (Life Technologies) containing 10% fetal bovine serum (Gibco, Waltham, MA; Thermo Fisher Scientific) and 100 U/mL penicillin-streptomycin (Thermo Fisher Scientific). 30 …”