Irreversible Photoreceptors and RPE Cells Damage by Intravenous Sodium Iodate in Mice Is Related to Macrophage Accumulation

Moriguchi, Mayu; Nakamura, Shinsuke; Inoue, Yuki; Nishinaka, Anri; Nakamura, Maho; Shimazawa, Masamitsu; Hara, Hideaki

doi:10.1167/iovs.17-23532

Cited by 58 publications

(74 citation statements)

References 48 publications

(58 reference statements)

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“…Of note, in our present study transcription levels of properdin-treated cells were always reversed after 24 h compared to 4 h. Our assumption of a tightly regulated time-dependent complement expression profile in the RPE and retina was further supported by others showing that complement inhibiting components peaked simultaneously with photoreceptor apoptosis after light-induced retinal damage in rats [ 83 ]. A similar effect was observed for expression of AMD-related genes and cytokines in mice after intravenous sodium iodate injection [ 84 ].…”

Section: Discussionsupporting

confidence: 74%

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

et al. 2020

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The retinal pigment epithelium (RPE) maintains visual function and preserves structural integrity of the retina. Chronic dysfunction of the RPE is associated with retinal degeneration, including age-related macular degeneration (AMD). The AMD pathogenesis includes both increased oxidative stress and complement dysregulation. Physiological sources of oxidative stress in the retina are well known, while complement sources and regulation are still under debate. Using human primary RPE (hpRPE) cells, we have established a model to investigate complement component expression on transcript and protein level in AMD-risk and non-risk hpRPE cells. We evaluated the effect of properdin, a complement stabilizer, on the hpRPE cell-dependent complement profile exposed to oxidative stress. hpRPE cells expressed complement components, receptors and regulators. Complement proteins were also stored and secreted by hpRPE cells. We associated AMD-risk single nucleotide polymorphisms with an increased secretion of complement factors D (CFD) and I (CFI). Furthermore, we detected hpRPE cell-associated complement activation products (C3a, C5a) independent of any extracellularly added complement system. Exogenous properdin increased the mRNA expression of CFI and CFD, but decreased levels of complement components (C1Q, C3), receptors (C3AR, C5AR1, CD11B) and inflammation-associated transcripts (NLRP3, IL1B) in hpRPE cells exposed to oxidative stress. This properdin effect was time-dependently counter regulated. In conclusion, our data unveiled a local, genotype-associated complement component production in hpRPE cells, regulated by exogenous properdin. The local complement production and activation via blood-independent mechanisms can be a new therapeutic target for AMD.

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Section: Discussionsupporting

confidence: 74%

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

et al. 2020

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“…We next performed an intraperitoneal injection of NaIO 3 to cause retinal fibrosis secondary to RPE damage and photoreceptor degeneration in mice 51 . Normal RPE cells strongly expressed RPE65 (Figure 8 A) along with a regular alignment of photoreceptor apical processes (Figure 8 B).…”

Section: Resultsmentioning

confidence: 99%

“…We used a mouse model of Müller cell gliosis caused by intraperitoneal NaIO 3 to study changes in Notch and TGFβ signaling and tested the effects of intravitreal injection of RO4929097 on Müller cell gliosis. NaIO 3 is a chemical oxidizing agent that was reported to primarily damage the RPE, leading to subsequent photoreceptor degeneration and alterations in retinal structures including Müller cell gliosis 51 , 59 - 61 . Müller cell gliosis has been found on the surface of the retina and in the subretinal space in a previous study using the NaIO 3 -induced retinal damage model in rabbits 61 .…”

Section: Discussionmentioning

confidence: 99%

Targeting the Notch and TGF-β signaling pathways to prevent retinal fibrosis in vitro and in vivo

Fan¹,

Shen²,

Lee³

et al. 2020

Theranostics

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Rationale: The Notch and transforming growth factor-β (TGFβ) signaling pathways are two intracellular mechanisms that control fibrosis in general but whether they play a major role in retinal fibrosis is less clear. Here we study how these two signaling pathways regulate Müller cell-dominated retinal fibrosis in vitro and in vivo . Methods: Human MIO-M1 Müller cells were treated with Notch ligands and TGFβ1, either alone or in combination. Western blots were performed to study changes in γ-secretase proteases, Notch downstream effectors, endogenous TGFβ1, phosphorylated Smad3 (p-Smad3) and extracellular matrix (ECM) proteins. We also studied the effects of RO4929097, a selective γ-secretase inhibitor, on expression of ECM proteins after ligand stimulation. Müller cell viability was studied by AlamarBlue and cytotoxicity by lactate cytotoxicity assays. Finally, we studied changes in Notch and TGFβ signaling and tested the effect of intravitreal injections of the Notch pathway inhibitor RO4929097 on retinal fibrosis resulted from Sodium iodate (NaIO 3 )-induced retinal injury in mice. We also studied the safety of intravitreal injections of RO4929097 in normal mice. Results: Treatment of Müller cells with Notch ligands upregulated γ-secretase proteases and Notch downstream effectors, with increased expression of endogenous TGFβ1, TGFβ receptors and p-Smad3. TGFβ1 upregulated the expression of proteins associated with both signaling pathways in a similar manner. Notch ligands and TGFβ1 had additive effects on overexpression of ECM proteins in Müller cells which were inhibited by RO4929097. Notch and TGFβ ligands stimulated Müller cell proliferation which was inhibited by RO4929097 without damaging the cells. NaIO 3 -induced retinal injury activated both Notch and TGFβ signaling pathways in vivo . Intravitreal injection of RO4929097 prevented Müller cell gliosis and inhibited overexpression of ECM proteins in this murine model. We found no safety concerns for up to 17 days after an intravitreal injection of RO4929097. Conclusions: Inhibiting Notch signaling might be an effective way to prevent retinal fibrosis. This study is of clinical significance in developing a treatment for preventing fibrosis in proliferative vitreoretinopathy, proliferative diabetic retinopathy and wet age-related macular degeneration.

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“…The implication for our data is that TLR2 deficiency may result in reduced macrophage and microglial infiltration to the retina in response to oxidative stress. A recent report has demonstrated that photoreceptor cell death in the NaIO 3 model is correlative with activated macrophage accumulation in the outer retina after RPE degeneration (Moriguchi et al, 2018). We next assessed the extent to which absence of TLR2 might influence macrophage/microglial cell migration into the outer retina, in response to oxidative stress.…”

Section: Tlr2 Deficiency Delays Naio 3 -Induced Iba1+mentioning

confidence: 99%

Toll-like Receptor 2 Facilitates Oxidative Damage-Induced Retinal Degeneration

et al. 2020

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Graphical Abstract Highlights d TLR2 activates the alternative complement pathway d TLR2 signaling triggers sub-lytic MAC formation on retinal pigment epithelial cells d TLR2 deficiency reduces oxidative stress-induced C3 and MAC in the outer retina d TLR2 blockade protects photoreceptors and RPE from oxidative stress-induced cell death SUMMARY Retinal degeneration is a form of neurodegenerative disease and is the leading cause of vision loss globally. The Toll-like receptors (TLRs) are primary components of the innate immune system involved in signal transduction. Here we show that TLR2 induces complement factors C3 and CFB, the common and rate-limiting factors of the alternative pathway in both retinal pigment epithelial (RPE) cells and mononuclear phagocytes. Neutralization of TLR2 reduces opsonizing fragments of C3 in the outer retina and protects photoreceptor neurons from oxidative stress-induced degeneration. TLR2 deficiency also preserves tight junction expression and promotes RPE resistance to fragmentation. Finally, oxidative stress-induced formation of the terminal complement membrane attack complex and Iba1+ cell infiltration are strikingly inhibited in the TLR2-deficient retina. Our data directly implicate TLR2 as a mediator of retinal degeneration in response to oxidative stress and present TLR2 as a bridge between oxidative damage and complement-mediated retinal pathology.

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Irreversible Photoreceptors and RPE Cells Damage by Intravenous Sodium Iodate in Mice Is Related to Macrophage Accumulation

Abstract: The NaIO3-induced retinal damage was reversible at low concentrations but permanent at high concentrations of NaIO3. The accumulation of macrophages around the RPE cells caused the photoreceptor cell death.

Cited by 58 publications

References 48 publications

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

Targeting the Notch and TGF-β signaling pathways to prevent retinal fibrosis in vitro and in vivo

Toll-like Receptor 2 Facilitates Oxidative Damage-Induced Retinal Degeneration

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