Novel Role for the Innate Immune Receptor Toll-Like Receptor 4 (TLR4) in the Regulation of the Wnt Signaling Pathway and Photoreceptor Apoptosis

Hyun Yi,Abigail S Hackam,David J Hackam,Chhinder P Sodhi,Amit K Patel,Mauricio Martins Rodrigues

doi:10.1371/journal.pone.0036560

Hyun Yi, Abigail S Hackam + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0036560

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Journal: PLoS ONE	Publication Date: May 17, 2012
Citations: 59	License type: CC BY 4.0

Affiliation: University of Miami, University of Pittsburgh

Abstract

Recent evidence has implicated innate immunity in regulating neuronal survival in the brain during stroke and other neurodegenerations. Photoreceptors are specialized light-detecting neurons in the retina that are essential for vision. In this study, we investigated the role of the innate immunity receptor TLR4 in photoreceptors. TLR4 activation by lipopolysaccharide (LPS) significantly reduced the survival of cultured mouse photoreceptors exposed to oxidative stress. With respect to mechanism, TLR4 suppressed Wnt signaling, decreased phosphorylation and activation of the Wnt receptor LRP6, and blocked the protective effect of the Wnt3a ligand. Paradoxically, TLR4 activation prior to oxidative injury protected photoreceptors, in a phenomenon known as preconditioning. Expression of TNFα and its receptors TNFR1 and TNFR2 decreased during preconditioning, and preconditioning was mimicked by TNFα antagonists, but was independent of Wnt signaling. Therefore, TLR4 is a novel regulator of photoreceptor survival that acts through the Wnt and TNFα pathways.

Highlights

Toll-like receptors (TLRs) are essential mediators of innate and adaptive immunity in the defence against invading pathogens
TLRs in the central nervous system (CNS) are activated by endogenous molecules released from injured cells that act as danger signals, known as damage-associated molecular patterns (DAMPs) [1,3,4,5]
We showed that activation of the innate immunity Toll-Like Receptor 4 (TLR4) receptor has a dual role in regulating photoreceptor survival

Summary

Introduction

Toll-like receptors (TLRs) are essential mediators of innate and adaptive immunity in the defence against invading pathogens. TLRs are highly expressed on immune cells that have pathogen surveillance activity [1,2]. TLR4 in particular is increasingly being recognized as a modulator of neuronal survival in the brain during non-pathogen (sterile) injuries [6]. Excessive activation of TLR4 and other TLRs induces expression of cytokines and pro-inflammatory molecules, resulting in further neuronal damage [10]. Induction of the TLR4 innate immunity pathway during oxidative and ischemic injuries promotes severe axonal and neuronal loss [9,11,12,13,14]. Mice lacking TLR4 show reduced neuronal apoptosis and decreased pathology in the retina and brain [13,14], which lends further support for a pathologic role of TLR4 in neuronal injury

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