The Wnt/β-Catenin Pathway Cross-Talks with STAT3 Signaling to Regulate Survival of Retinal Pigment Epithelium Cells

Fragoso, Miryam A.; Patel, Amit K.; Nakamura, Rei; Yi, Hyun; Surapaneni, Krishna; Hackam, Abigail S.

doi:10.1371/journal.pone.0046892

Cited by 66 publications

(71 citation statements)

References 54 publications

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“…We identified STAT3 as a necessary component in TLR3 induced protection during injury. To our knowledge, this is the first study to link Stat3 protection to an immune mediated protective response in neurons, and is supported by a vast literature on the protective role of Stat3 signaling in neurodegeneration and retinal health (Zhang et al, 2008; Fragoso et al, 2012; Patel and Hackam, 2012). We observed that neither TLR3 activation nor oxidative stress induced significant increases in Stat3 activation; however, the combination of these two pathways triggers increased Stat3 signaling.…”

Section: Discussionmentioning

confidence: 55%

A novel protective role for the innate immunity Toll-Like Receptor 3 (TLR3) in the retina via Stat3

Patel

Hackam

2014

Molecular and Cellular Neuroscience

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The innate immune system and inflammatory pathways play key roles in numerous diseases of the central nervous system (CNS). Recent evidence indicates that innate immunity induces both pathogenesis and protection during neuronal injury. To test the possibility that the conflicting roles of innate immunity in the CNS depends on the cellular environment in which innate immunity is stimulated, we analyzed the effect of toll-like receptor 3 (TLR3) activation on neuronal survival in the presence and absence of oxidative injury in a mouse model system. We demonstrated that activation of TLR3 by the double stranded RNA activator, Poly (I:C), during paraquat induced oxidative stress, significantly protected mouse photoreceptors, as measured by increased retinal structure, function, and improved visual acuity. In contrast, TLR3 activation without concurrent oxidative injury was neurotoxic. The neurotoxic and protective effects of Poly (I:C) stimulation were absent in TLR3 knockout animals, which indicates that protection by Poly (I:C) is dependent on the TLR3 signaling pathway. Furthermore, we identified the pro-survival transcription factor Stat3 as a necessary mechanism for protection. Knockdown of Stat3 using lentivirally delivered shRNA abolished the protective effects of TLR3 signaling in the retina during oxidative stress. Therefore, TLR3 activation in the context of oxidative stress triggers protective instead of pathogenic signaling, suggesting that TLR3 is a potential therapeutic target for neurodegeneration where oxidative stress is a significant contributor.

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Section: Discussionmentioning

confidence: 55%

A novel protective role for the innate immunity Toll-Like Receptor 3 (TLR3) in the retina via Stat3

Patel

Hackam

2014

Molecular and Cellular Neuroscience

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“…The transcription factor Stat3 plays a role in axonal regrowth (Pellegrino and Habecker, 2013, Qin et al, 2013) and Stat3 is induced by Wnt3a and contributes to Wnt3a-mediated survival of multiple retinal cell types (Fragoso et al, 2012, Patel and Hackam, 2012, 2014b, Patel et al, 2015b). To determine whether the Stat3 pathway contributes to Wnt3a-induced RGC survival and axonal growth after injury, we first tested whether Wnt3a activates Stat3 signaling in the retina.…”

Section: Resultsmentioning

confidence: 99%

“…Wnt3a may also indirectly promote regeneration by inducing expression of its target genes such as pro-regeneration molecules STAT3, CNTF and neurotrophins (Fragoso et al, 2012, Yi et al, 2012a, Patel et al, 2015b). Furthermore, Wnt signaling could be enhanced through endogenous regulation of Wnt antagonists, such as through microRNA-431-mediated targeting of the Wnt inhibitor Kremen1, as observed with axon regeneration of sensory neurons (Wu and Murashov, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Wnt signaling is active in RGCs in the adult mouse retina (Liu et al, 2006, Yi et al, 2007), it induces expression of genes that have pro-regenerative properties, such as STAT3 and CNTF (Seitz et al, 2010, Fragoso et al, 2012) and is suppressed by genes that inhibit regeneration, such as KLF4 and ephrins (Schmitt et al, 2006, Cui et al, 2013). Also, Wnt3a may directly regulate growth cone remodeling by altering microtubule stability through differential binding of its downstream components, APC and Dvl1, to the positive ends of microtubules (Purro et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Wnt signaling promotes axonal regeneration following optic nerve injury in the mouse

2017

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Adult mammalian CNS axons generally do not regenerate, creating an obstacle to effective repair and recovery after neuronal injury. The canonical Wnt/β-catenin signaling pathway is an essential signal transduction cascade that regulates axon growth and neurite extension in the developing mammalian embryo. In this study, we investigated whether a Wnt/β-catenin signaling activator could be repurposed to induce regeneration in the adult CNS after axonal injury. We used a retinal ganglion cell (RGC) axon crush injury model in a transgenic Wnt reporter mouse, and intravitreal injections were used to deliver Wnt3a or saline to the RGC cell bodies within the retina. Our findings demonstrated that Wnt3a induced Wnt signaling in RGCs and resulted in significant axonal regrowth past the lesion site when measured at two and four weeks post-injury. Furthermore, Wnt3a-injected eyes showed increased survival of RGCs and significantly higher PERG amplitudes compared to the control. Additionally, Wnt3a-induced axonal regeneration and RGC survival was associated with elevated activation of the transcription factor Stat3, and reducing expression of Stat3 using a conditional Stat3 knock-out mouse line led to diminished Wnt3a-dependent axonal regeneration and RGC survival. Therefore, these findings reveal a novel role for retinal Wnt signaling in axonal regrowth and RGC survival following axonal injury, which may lead to the development of novel therapies for axonal regeneration.

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“…To activate Wnt/β-catenin signaling pathway, BMSCs were treated with 20 µM BIO (Sigma) for 24 h [36,37]. …”

Section: Methodsmentioning

confidence: 99%

Reciprocal Interferences of TNF-α and Wnt1/β-Catenin Signaling Axes Shift Bone Marrow-Derived Stem Cells Towards Osteoblast Lineage after Ethanol Exposure

Chen¹,

Chen

Yin

et al. 2013

Cell Physiol Biochem

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Background/Aims: We have reported in a separate study that alcohol exposure triggers activation of the TNF-α signaling pathway leading to an adverse shift of multipotential mesenchymal stem cells in bone marrow (BMSCs) away from osteogenesis towards adipogenesis. However, inhibition of TNF-α signaling only yielded moderate inhibition of adipogenesis. Here we showed that in addition to promoting the TNF-α signaling, alcohol also suppressed the Wnt1/β-catenin signaling pathway. Methods: We treated primary BMSCs from human subjects with alcohol for 24 days. We measured changes of genes related to endoplasmic reticulum (ER) stress, adipogenic markers and osteogenic markers using quantitative real-time RT-PCR and Western blot analysis. We performed Alizarin red staining for osteogenesis. We also conducted assays for osteogenic biomarkers alkaline phosphatase, collagen-I and osteocalcin. Results: Wnt/β-catenin signaling was markedly activated in BMSCs treated with osteogenic inducers relative to the control cells, as indicated by the increased levels of nuclear β-catenin along with reduced levels of cytosolic β-catenin, as well as increased protein levels of Wnt1. Activation of Wnt/β-catenin signaling was significantly suppressed in BMSCs exposed to alcohol, which was reflected by downregulated expression of osteogenic marker genes Osf2/Cbfa1, osteopontin and osteocalcin, upregulated adipogenic marker PPARγ2 and aP2, and reduced number of calcifcation nodules. In contrast, activation of Wnt/β-catenin signaling by BIO favored osteogenesis even in the presence of alcohol. Simultaneous activation of Wnt1 by BIO and inhibition of TNF-α by 3,6'-dithiothalidomide produced synergetic suppression of ethanol-induced adipogenic lineage compared to interference with either of them alone. Conclusion: This remarkable shift of BMSCs towards osteoblast lineage suggests the superiority of concordant and reciprocal interferences of the TNF-α and Wnt/β-catenin pathways for promoting osteogenesis.

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The Wnt/β-Catenin Pathway Cross-Talks with STAT3 Signaling to Regulate Survival of Retinal Pigment Epithelium Cells

Cited by 66 publications

References 54 publications

A novel protective role for the innate immunity Toll-Like Receptor 3 (TLR3) in the retina via Stat3

A novel protective role for the innate immunity Toll-Like Receptor 3 (TLR3) in the retina via Stat3

Wnt signaling promotes axonal regeneration following optic nerve injury in the mouse

Reciprocal Interferences of TNF-α and Wnt1/β-Catenin Signaling Axes Shift Bone Marrow-Derived Stem Cells Towards Osteoblast Lineage after Ethanol Exposure

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