The Role of TLR4 Activation in Photoreceptor Mitochondrial Oxidative Stress

Ko, MinHee K.; Saraswathy, Sindhu; Parikh, Jignesh; Rao, Narsing A.

doi:10.1167/iovs.10-6357

Cited by 51 publications

(43 citation statements)

References 54 publications

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“…Studies other than single nucleotide polymorphism analyses are needed to resolve this discrepancy. Additional evidence for the role of TLRs in retinal physiology and pathology has been reported (75)(76)(77)(78). Possible contributions of TLRs to the pathogenesis of neurodegeneration and heart disease have also been discussed (79,80), and endogenous ligands for these receptors have been identified (47,81).…”

Section: Rdh8mentioning

confidence: 99%

Photoreceptor Proteins Initiate Microglial Activation via Toll-like Receptor 4 in Retinal Degeneration Mediated by All-trans-retinal

Kohno¹,

Chen²,

Kevany³

et al. 2013

Journal of Biological Chemistry

157

190

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Background:The host inflammatory response can contribute to the pathogenesis of retinal degeneration. Results: Photoreceptor proteins in degenerating retinas can activate microglial cells through Toll-like receptor 4 (Tlr4). Conclusion: Microglial activation can be a common pathology of retinal degeneration. Significance: Modulating microglial activation is a potential treatment strategy for human retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa.

show abstract

Section: Rdh8mentioning

confidence: 99%

Photoreceptor Proteins Initiate Microglial Activation via Toll-like Receptor 4 in Retinal Degeneration Mediated by All-trans-retinal

Kohno¹,

Chen²,

Kevany³

et al. 2013

Journal of Biological Chemistry

157

190

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“…activated in the apoptotic process and subsequently processes executioner caspases 3 (28,30). These steps are all essential for apoptosis induction.…”

mentioning

confidence: 99%

Critical role of myeloid differentiation factor 88 in necrotizing enterocolitis

et al. 2014

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Background:The importance of Toll-like receptor 4 in necrotizing enterocolitis (NEC) has been intensively studied, but its downstream signaling and the potential regulatory mechanisms remain unidentified. Our study focused on the role of myeloid differentiation factor 88 (MyD88), the first downstream adaptor of Toll-like receptor 4 inflammatory and apoptotic signaling in the pathogenesis of NEC. Methods: MyD88 knockout (MyD88−/− -Ko) mice and lentivirus-mediated stable MyD88-knockdown cell line (IEC-6) were used. NEC was induced by formula gavage, cold, hypoxia, combined with lipopolysaccharide (LPS) in vivo, or LPS stimulation in vitro. NEC was evaluated by histology and multiple inflammatory cytokines. Enterocyte apoptosis was evaluated by terminal-deoxynucleoitidyl transferase-mediated nick end labeling (TUNEL) or Annexin analysis. Inflammatory or apoptotic molecules including NF-κB, Toll/IL-1R domain-containing adaptor-inducing IFN-β, interferon regulatory factor 3, Bax, Bcl-2, and caspases were examined by quantitative real-time PCR (qRT-PCR). results: In the MyD88-Ko group, NEC severity and intestinal enterocyte apoptosis rate were reduced, the expression of NF-κB, caspases, and Bax, were all downregulated, while Toll/ IL-1R domain-containing adaptor-inducing IFN-β and interferon regulatory factor 3 were upregulated, and antiapoptotic gene Bcl-2 remained stable. Cytokine levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α) were also all decreased. conclusion: MyD88-dependent signaling is the prevailing inflammatory and apoptotic signaling in Toll-like receptor 4 downstream signaling; MyD88-Ko resulted in reduced inflammatory severity and apoptosis, though MyD88-independent signaling can also be activated, but is of less dominant for the development of NEC.

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“…[31][32][33][34] Moreover, it has been reported that proinflammatory cytokines, such as transforming growth factor (TGF)-β1, interleukin (IL)-1β, and IL-6, were rapidly upregulated under ischemic conditions in astrocytes or Müllers cells, microglia, and endothelial cells in the retina in rat and mouse models. 35,36 TLR4 signaling activation might be connected with the upregulation of those proinflammatory or angiogenic cytokines.…”

mentioning

confidence: 99%

Angiogenesis Mediated by Toll-Like Receptor 4 in Ischemic Neural Tissue

Sun

Ren

Lin

et al. 2013

ATVB

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Objective-Activation of the immune system via toll-like receptors (TLRs) is implicated in atherosclerosis, microvascular complications, and angiogenesis. However, the involvement of TLRs in inflammation-associated angiogenesis in ischemic neural tissue has not been investigated. The goal of this study is to determine the role of TLR4 signaling in oxygeninduced neovascularization in retina, a neural tissue. Methods and Results-In oxygen-induced retinopathy model, we found that retinal neovascularization was significantly attenuated in TLR4 −/− mice. The further study revealed that the absence of TLR4 led to downregulation of proinflammatory factors in association with the attenuated activation of glia in the ischemic retina, which was also associated with reduced expression of high-mobility group box-1, an endogenous ligand for TLR4. The application of high-mobility group box-1 to the ischemic retina promoted the production of proinflammatory factors in wild-type but not TLR4 −/− mice. Highmobility group box-1 treatment in vitro also significantly promoted the production of proinflammatory factors in retinal glial cells from wild-type mice, but much less from TLR4 −/− mice. Conclusion-Our results suggest that the release of high-mobility group box-1 in ischemic neural tissue initiates TLR4-dependent responses that contribute to neovascularization. These findings represented a previously unrecognized effect of TLR4 on angiogenesis in association with the activation of glia in ischemic neural tissue.

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The Role of TLR4 Activation in Photoreceptor Mitochondrial Oxidative Stress

Abstract: Retinal photoreceptors are susceptible to mitochondrial oxidative stress/mtDNA damage in robust TLR4-mediated innate immune response.

Cited by 51 publications

References 54 publications

Photoreceptor Proteins Initiate Microglial Activation via Toll-like Receptor 4 in Retinal Degeneration Mediated by All-trans-retinal

Photoreceptor Proteins Initiate Microglial Activation via Toll-like Receptor 4 in Retinal Degeneration Mediated by All-trans-retinal

Critical role of myeloid differentiation factor 88 in necrotizing enterocolitis

Angiogenesis Mediated by Toll-Like Receptor 4 in Ischemic Neural Tissue

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