Toll-Like Receptor 3 Activation Initiates Photoreceptor Cell Death In Vivo and In Vitro.
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 immunity-mediated inflammatory response. However, its role in photoreceptor cells, the effectors of AMD geographic atrophy, remains unclear.



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 polyinosine-polycytidylic 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.



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.



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.
Lab for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research, Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Mei-Ling
ML
Gao
Lab for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research, Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Kun-Chao
KC
Wu
Lab for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research, Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Wen-Li
WL
Deng
Lab for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research, Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Xin-Lan
XL
Lei
Lab for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research, Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Lue
L
Xiang
Lab for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research, Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Gao-Hui
GH
Zhou
Lab for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research, Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Chun-Yun
CY
Feng
Lab for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research, Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Xue-Wen
XW
Cheng
Lab for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research, Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Chang-Jun
CJ
Zhang
Gu Laboratory, The Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Feng
F
Gu
Department of Surgical Retina, The Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Rong-Han
RH
Wu
Lab for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research, Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Zi-Bing
ZB
Jin
D000704:Analysis of Variance; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004596:Electroretinography; D007369:Interferon Inducers / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D017423:Sequence Analysis, RNA; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D041623:Tomography, Optical Coherence
D018925:Chemokines; D016207:Cytokines; D007369:Interferon Inducers; D051196:Toll-Like Receptor 3; D011070:Poly I-C