TLR3 And AMD

TLR3 and AMDPeng ZHOU, M.D. Xiao-Xin LI, M.D.

Department of OphthalmologyEye and ENT Hospital of Fudan UniversityShanghai, P.R. China

April 8, 2023

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Toll-like Receptor 3 (TLR3)Pattern recognition receptors

of the innate immune system

Horseshoe shape

Recognizes double-stranded RNA (dsRNA)

induces the activation of NF-κB

and the production of type I interferons

Play a role in host defense against viruses

2012年眼底血管性疾病学习班及老年黄斑病变论坛

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TLR3 and Dry AMD

TLR3 and Wet AMD

TLR3 and dsRNA


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TLR3 and Dry AMD

TLR3 and Wet AMD

TLR3 and dsRNA


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TLR3 and Dry AMD

V.S.


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6TLR3 rs5743391 Protects Against Dry AMD


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How to protect?

Step by step:

G

1234CmRNA

Nuclei

412L

DNA

TLR3

NFkB

Dry AMD


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Plasmids

G

1234CmRNA

Nuclei

412L

DNA

TLR3

NFkB

Dry AMD


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mRNA: RT-PCR

G

1234CmRNA

Nuclei

412L

DNA

TLR3

NFkB

Dry AMD


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Protein: Western Blot

G

1234CmRNA

Nuclei

412L

DNA

TLR3

NFkB

Dry AMD


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11Surface

expression:Flow cytometry

G

1234CmRNA

Nuclei

412L

DNA

TLR3

NFkB

Dry AMD


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dsRNA Binding:REMSA

G

1234CmRNA

Nuclei

412L

DNA

TLR3

NFkB

Dry AMD


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13NFkB:

Luciferase assays& EMSA

G

1234CmRNA

Nuclei

412L

DNA

TLR3

NFkB

Dry AMD


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TLR3 rs5743391 = 50% TLR3

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TLR3 and Dry AMD

TLR3 and Wet AMD

TLR3 and dsRNA


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1. Kleinman ME et.al Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature. 2008 Apr 3;452(7187):591-72. Cole JE, et.al Unexpected protective role for Toll-like receptor 3 in the arterial wall. Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2372-7.

V.S.

TLR3 and Wet AMD?Theoretically…

1: Protect against CNV? 2. Risk Factor?

TLR3 rs5743391 =Risk Factor

TLR3 rs5743391 = 50% TLR3

V.S.TLR3 rs5743391 =

Protect against CNV

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TLR3 rs5743391 and Wet AMD


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TLR3 rs5743391 Protects against Wet AMD


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1. Kleinman ME et.al Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature. 2008 Apr 3;452(7187):591-72. Cole JE, et.al Unexpected protective role for Toll-like receptor 3 in the arterial wall. Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2372-7.

TLR3 and Wet AMDTheoretically…

1: Protect against CNV 2. Risk Factor

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21Our Samples:

CNV-PCV-Control 95 : 92 : 95

g. - 855 A>G ， Novel


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In the near future:Needs more samples to confirm

new findings

Investigate the function of the above novel SNP and rs5743391


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TLR3 and Dry AMD

TLR3 and Wet AMD

TLR3 and dsRNA


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Where the dsRNAs come from?

G

1234CmRNA

Nuclei

412L

DNA

TLR3

NFkB

Dry AMD


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Alu RNA?

Noncoding RNAs

Accumulation of Alu RNA transcripts in the RPE GA

Does Not Activate TLR3


1. Tarallo V, et.al DICER1 Loss and Alu RNA Induce Age-Related Macular Degeneration via the NLRP3 Inflammasome and MyD88. Cell. 2012 May 11;149(4):847-592. Kaneko, H. et.al DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 2011.471, 325–330.uce

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Other dsRNA?


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SummaryTLR3 rs5743391 protects against dry AMD

through decreased dsRNA binding capacity

TLR3 rs5743391 may protects against wet AMD

However, the mechanism needs further investigation

The resource of dsRNA needs further investigation


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Thank You!


TLR3 And AMD

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