Toll-like receptor 3 (TLR3) protects retinal pigmented epithelium (RPE) cells from oxidative stress through a STAT3-dependent mechanism

Amit K. Patel, Abigail S Hackam

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Toll-like receptors (TLRs) are essential receptors of the innate immune system and are first responders for protection against bacterial and viral pathogens. Recently, several TLRs have also been implicated in regulating cell death and survival in non-pathogen injuries such as stroke and oxidative stress. Investigating the role of TLRs during central nervous system damage is an important focus of research that may reveal new mechanisms underlying the cellular response to injury and survival. Retinal pigmented epithelium (RPE) cells form an epithelial layer underneath the neural retina that maintains the function of photoreceptors and are the primary cell type affected in the retinal disease age-related macular degeneration (AMD). Predicted loss of function polymorphisms in the TLR3 gene are associated with protection from AMD but the role of TLR3 in regulating RPE survival during AMD-like injury, such as high oxidative stress, is not known. Therefore the purpose of this study is to evaluate the effect of TLR3 signaling on RPE viability during oxidative stress. We demonstrated that TLR3 activation in the presence of oxidative stress injury significantly increased RPE cell viability, in contrast to TLR3 reducing cell viability in the absence of cellular injury. Furthermore, we show signal transducer and activator of transcription 3 (STAT3) signaling as an essential mediator of TLR3-regulated protection of RPE cells. STAT3 signaling was increased by TLR3 activation and knockdown of STAT3 transcripts using siRNA abolished the protective effect of TLR3 during oxidative stress. Together, these results demonstrate a novel pro-survival role for TLR3 signaling within the RPE during injury. These findings support the concept that dysregulation of TLR3 activity may contribute to the development of AMD, suggesting that precise regulation of the TLR3 pathway during AMD-associated injury could be of therapeutic interest.

Original languageEnglish
Pages (from-to)122-131
Number of pages10
JournalMolecular Immunology
Volume54
Issue number2
DOIs
StatePublished - Jun 1 2013

Fingerprint

Toll-Like Receptor 3
STAT3 Transcription Factor
Oxidative Stress
Epithelium
Macular Degeneration
Wounds and Injuries
Toll-Like Receptors
Cell Survival
Retinal Diseases
Photoreceptor Cells
Small Interfering RNA
Retina
Immune System

Keywords

  • Oxidative stress
  • Retinal pigmented epithelium
  • STAT3
  • Toll-like receptor 3

ASJC Scopus subject areas

  • Molecular Biology
  • Immunology

Cite this

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abstract = "Toll-like receptors (TLRs) are essential receptors of the innate immune system and are first responders for protection against bacterial and viral pathogens. Recently, several TLRs have also been implicated in regulating cell death and survival in non-pathogen injuries such as stroke and oxidative stress. Investigating the role of TLRs during central nervous system damage is an important focus of research that may reveal new mechanisms underlying the cellular response to injury and survival. Retinal pigmented epithelium (RPE) cells form an epithelial layer underneath the neural retina that maintains the function of photoreceptors and are the primary cell type affected in the retinal disease age-related macular degeneration (AMD). Predicted loss of function polymorphisms in the TLR3 gene are associated with protection from AMD but the role of TLR3 in regulating RPE survival during AMD-like injury, such as high oxidative stress, is not known. Therefore the purpose of this study is to evaluate the effect of TLR3 signaling on RPE viability during oxidative stress. We demonstrated that TLR3 activation in the presence of oxidative stress injury significantly increased RPE cell viability, in contrast to TLR3 reducing cell viability in the absence of cellular injury. Furthermore, we show signal transducer and activator of transcription 3 (STAT3) signaling as an essential mediator of TLR3-regulated protection of RPE cells. STAT3 signaling was increased by TLR3 activation and knockdown of STAT3 transcripts using siRNA abolished the protective effect of TLR3 during oxidative stress. Together, these results demonstrate a novel pro-survival role for TLR3 signaling within the RPE during injury. These findings support the concept that dysregulation of TLR3 activity may contribute to the development of AMD, suggesting that precise regulation of the TLR3 pathway during AMD-associated injury could be of therapeutic interest.",
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