scholarly journals Dorsal-Ventral Differences in Retinal Structure in the Pigmented Royal College of Surgeons Model of Retinal Degeneration

2021 ◽  
Vol 14 ◽  
Author(s):  
Una Greferath ◽  
Mario Huynh ◽  
Andrew Ian Jobling ◽  
Kirstan Anne Vessey ◽  
Gene Venables ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Royal College ◽  
Vision Loss ◽  
Mononuclear Phagocytes ◽  
Subretinal Space ◽  
Striking Difference ◽  
Recessive Mutation ◽  
Rcs Rat ◽  
Retinal Structure

Retinitis pigmentosa is a family of inherited retinal degenerations associated with gradual loss of photoreceptors, that ultimately leads to irreversible vision loss. The Royal College of Surgeon's (RCS) rat carries a recessive mutation affecting mer proto-oncogene tyrosine kinase (merTK), that models autosomal recessive disease. The aim of this study was to understand the glial, microglial, and photoreceptor changes that occur in different retinal locations with advancing disease. Pigmented RCS rats (RCS-p+/LAV) and age-matched isogenic control rdy (RCS-rdy +p+/LAV) rats aged postnatal day 18 to 6 months were evaluated for in vivo retinal structure and function using optical coherence tomography and electroretinography. Retinal tissues were assessed using high resolution immunohistochemistry to evaluate changes in photoreceptors, glia and microglia in the dorsal, and ventral retina. Photoreceptor dysfunction and death occurred from 1 month of age. There was a striking difference in loss of photoreceptors between the dorsal and ventral retina, with a greater number of photoreceptors surviving in the dorsal retina, despite being adjacent a layer of photoreceptor debris within the subretinal space. Loss of photoreceptors in the ventral retina was associated with fragmentation of the outer limiting membrane, extension of glial processes into the subretinal space that was accompanied by possible adhesion and migration of mononuclear phagocytes in the subretinal space. Overall, these findings highlight that breakdown of the outer limiting membrane could play an important role in exacerbating photoreceptor loss in the ventral retina. Our results also highlight the value of using the RCS rat to model sectorial retinitis pigmentosa, a disease known to predominantly effect the inferior retina.

scholarly journals Subretinal mononuclear phagocytes induce cone segment loss via IL-1β

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Chiara M Eandi ◽  
Hugo Charles Messance ◽  
Sébastien Augustin ◽  
Elisa Dominguez ◽  
Sophie Lavalette ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Transitional Zone ◽  
Mononuclear Phagocyte ◽  
Geographic Atrophy ◽  
Mononuclear Phagocytes ◽  
High Acuity ◽  
Human And Mouse

Photo-transduction in cone segments (CS) is crucial for high acuity daytime vision. For ill-defined reasons, CS degenerate in retinitis pigmentosa (RP) and in the transitional zone (TZ) of atrophic zones (AZ), which characterize geographic atrophy (GA). Our experiments confirm the loss of cone segments (CS) in the TZ of patients with GA and show their association with subretinal CD14+mononuclear phagocyte (MP) infiltration that is also reported in RP. Using human and mouse MPs in vitro and inflammation-prone Cx3cr1GFP/GFP mice in vivo, we demonstrate that MP-derived IL-1β leads to severe CS degeneration. Our results strongly suggest that subretinal MP accumulation participates in the observed pathological photoreceptor changes in these diseases. Inhibiting subretinal MP accumulation or Il-1β might protect the CS and help preserve high acuity daytime vision in conditions characterized by subretinal inflammation, such as AMD and RP.

scholarly journals Mutation of SLC7A14 Causes Auditory Neuropathy and Retinitis Pigmentosa Mediated by Lysosomal Dysfunction

2021 ◽  
Author(s):  
Kimberlee P Giffen ◽  
Yi Li ◽  
Huizhan Liu ◽  
Xiao-Chang Zhao ◽  
Chang-Jun Zhang ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Hair Cells ◽  
Vision Loss ◽  
Nutrient Sensing ◽  
Auditory Neuropathy ◽  
Recessive Mutation ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Cell Degeneration ◽  
Lysosomal Dysfunction

Lysosomes contribute to cellular homeostasis via processes including phagocytosis, macromolecule catabolism, secretion, and nutrient sensing mechanisms. Defective proteins related to lysosomal macromolecule catabolism are known to cause a broad range of lysosomal storage diseases. It is unclear, however, if mutations in genes in the autophagy-lysosomal pathway can cause syndromic disease. Here we show that SLC7A14, a transporter protein mediating lysosomal uptake of cationic amino acids, is evolutionarily conserved in vertebrate mechanosensitive hair cells and highly expressed in lysosomes of mammalian cochlear inner hair cells (IHCs) and retinal photoreceptors. Autosomal recessive mutation of SLC7A14 caused loss of IHCs and photoreceptors, leading to pre-synaptic auditory neuropathy and retinitis pigmentosa in mice and humans. Loss of function mutation altered protein trafficking and disrupted lysosomal homeostasis, resulting in dysregulation of basal autophagy and progressive cell degeneration. This study is the first to implicate autophagy-lysosomal dysfunction in syndromic hearing and vision loss in mice and humans. 

scholarly journals Cell Ferroptosis: New Mechanism and New Hope for Retinitis Pigmentosa

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2153
Author(s):  
Ming Yang ◽  
Kwok-Fai So ◽  
Wai-Ching Lam ◽  
Amy Cheuk Yin Lo
Keyword(s):  
Cell Death ◽  
Retinitis Pigmentosa ◽  
Photoreceptor Cell ◽  
Vision Loss ◽  
Peripheral Vision ◽  
Cell Damage ◽  
Research Area ◽  
Night Vision

Retinitis pigmentosa (RP) is a leading cause of inherited retinal degeneration, with more than 60 gene mutations. Despite the genetic heterogenicity, photoreceptor cell damage remains the hallmark of RP pathology. As a result, RP patients usually suffer from reduced night vision, loss of peripheral vision, decreased visual acuity, and impaired color perception. Although photoreceptor cell death is the primary outcome of RP, the underlying mechanisms are not completely elucidated. Ferroptosis is a novel programmed cell death, with characteristic iron overload and lipid peroxidation. Recent studies, using in vitro and in vivo RP models, discovered the involvement of ferroptosis-associated cell death, suggesting a possible new mechanism for RP pathogenesis. In this review, we discuss the association between ferroptosis and photoreceptor cell damage, and its implication in the pathogenesis of RP. We propose that ferroptotic cell death not only opens up a new research area in RP, but may also serve as a novel therapeutic target for RP.

scholarly journals Implication of N-Methyl-d-Aspartate Receptor in Homocysteine-Induced Age-Related Macular Degeneration

2021 ◽  
Vol 22 (17) ◽  
pp. 9356
Author(s):  
Yara A. Samra ◽  
Dina Kira ◽  
Pragya Rajpurohit ◽  
Riyaz Mohamed ◽  
Leah A. Owen ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Aspartate Receptor ◽  
Age Related ◽  
Retinal Structure

Age-related macular degeneration (AMD) is a leading cause of vision loss. Elevated homocysteine (Hcy) (Hyperhomocysteinemia) (HHcy) has been reported in AMD. We previously reported that HHcy induces AMD-like features. This study suggests that N-Methyl-d-aspartate receptor (NMDAR) activation in the retinal pigment epithelium (RPE) is a mechanism for HHcy-induced AMD. Serum Hcy and cystathionine-β-synthase (CBS) were assessed by ELISA. The involvement of NMDAR in Hcy-induced AMD features was evaluated (1) in vitro using ARPE-19 cells, primary RPE isolated from HHcy mice (CBS), and mouse choroidal endothelial cells (MCEC); (2) in vivo using wild-type mice and mice deficient in RPE NMDAR (NMDARR-/-) with/without Hcy injection. Isolectin-B4, Ki67, HIF-1α, VEGF, NMDAR1, and albumin were assessed by immunofluorescence (IF), Western blot (WB), Optical coherence tomography (OCT), and fluorescein angiography (FA) to evaluate retinal structure, fluorescein leakage, and choroidal neovascularization (CNV). A neovascular AMD patient’s serum showed a significant increase in Hcy and a decrease in CBS. Hcy significantly increased HIF-1α, VEGF, and NMDAR in RPE cells, and Ki67 in MCEC. Hcy-injected WT mice showed disrupted retina and CNV. Knocking down RPE NMDAR improved retinal structure and CNV. Our findings underscore the role of RPE NMDAR in Hcy-induced AMD features; thus, NMDAR inhibition could serve as a promising therapeutic target for AMD.

scholarly journals Zika virus induces neuronal and vascular degeneration in developing mouse retina

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Yi Li ◽  
Shuizhen Shi ◽  
Fan Xia ◽  
Chao Shan ◽  
Yonju Ha ◽  
...  
Keyword(s):  
Mouse Model ◽  
Zika Virus ◽  
Vision Loss ◽  
Vaccine Candidate ◽  
Mouse Retina ◽  
Retinal Inflammation ◽  
Retinal Structure ◽  
Underlying Mechanisms ◽  
Causative Link

AbstractZika virus (ZIKV), a mosquito-borne flavivirus, can cause severe eye disease and even blindness in newborns. However, ZIKV-induced retinal lesions have not been studied in a comprehensive way, mechanisms of ZIKV-induced retinal abnormalities are unknown, and no therapeutic intervention is available to treat or minimize the degree of vision loss in patients. Here, we developed a novel mouse model of ZIKV infection to evaluate its impact on retinal structure. ZIKV (20 plaque-forming units) was inoculated into neonatal wild type C57BL/6J mice at postnatal day (P) 0 subcutaneously. Retinas of infected mice and age-matched controls were collected at various ages, and retinal structural alterations were analyzed. We found that ZIKV induced progressive neuronal and vascular damage and retinal inflammation starting from P8. ZIKV-infected retina exhibited dramatically decreased thickness with loss of neurons, initial neovascular tufts followed by vessel dilation and degeneration, increased microglia and leukocyte recruitment and activation, degeneration of astrocyte network and gliosis. The above changes may involve inflammation and endoplasmic reticulum stress-mediated cell apoptosis and necroptosis. Moreover, we evaluated the efficacy of preclinical drugs and the safety of ZIKV vaccine candidate in this mouse model. We found that ZIKV-induced retinal abnormalities could be blocked by a selective flavivirus inhibitor NITD008 and a live-attenuated ZIKV vaccine candidate could potentially induce retinal abnormalities. Overall, we established a novel mouse model and provide a direct causative link between ZIKV and retinal lesion in vivo, which warrants further investigation of the underlying mechanisms of ZIKV-induced retinopathy and the development of effective therapeutics.

scholarly journals Cone photoreceptor dysfunction in retinitis pigmentosa revealed by optoretinography

2021 ◽  
Vol 118 (47) ◽  
pp. e2107444118
Author(s):  
Ayoub Lassoued ◽  
Furu Zhang ◽  
Kazuhiro Kurokawa ◽  
Yan Liu ◽  
Marcel T. Bernucci ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Adaptive Optics ◽  
Vision Loss ◽  
Photoreceptor Cells ◽  
Segment Length ◽  
Cone Photoreceptor ◽  
Cone Cells ◽  
Common Group ◽  
Cone Density

Retinitis pigmentosa (RP) is the most common group of inherited retinal degenerative diseases, whose most debilitating phase is cone photoreceptor death. Perimetric and electroretinographic methods are the gold standards for diagnosing and monitoring RP and assessing cone function. However, these methods lack the spatial resolution and sensitivity to assess disease progression at the level of individual photoreceptor cells, where the disease originates and whose degradation causes vision loss. High-resolution retinal imaging methods permit visualization of human cone cells in vivo but have only recently achieved sufficient sensitivity to observe their function as manifested in the cone optoretinogram. By imaging with phase-sensitive adaptive optics optical coherence tomography, we identify a biomarker in the cone optoretinogram that characterizes individual cone dysfunction by stimulating cone cells with flashes of light and measuring nanometer-scale changes in their outer segments. We find that cone optoretinographic responses decrease with increasing RP severity and that even in areas where cone density appears normal, cones can respond differently than those in controls. Unexpectedly, in the most severely diseased patches examined, we find isolated cones that respond normally. Short-wavelength–sensitive cones are found to be more vulnerable to RP than medium- and long-wavelength–sensitive cones. We find that decreases in cone response and cone outer-segment length arise earlier in RP than changes in cone density but that decreases in response and length are not necessarily correlated within single cones.

scholarly journals Monocyte tissue factor induction by lipopolysaccharide (LPS): dependence on LPS-binding protein and CD14, and inhibition by a recombinant fragment of bactericidal/permeability-increasing protein

Blood ◽  
1994 ◽  
Vol 83 (9) ◽  
pp. 2516-2525 ◽  
Author(s):  
K Meszaros ◽  
S Aberle ◽  
R Dedrick ◽  
R Machovich ◽  
A Horwitz ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Binding Protein ◽  
Mononuclear Phagocytes ◽  
Factor Vii ◽  
Peripheral Blood Mononuclear ◽  
Recombinant Fragment

Abstract Mononuclear phagocytes, stimulated by bacterial lipopolysaccharide (LPS), have been implicated in the activation of coagulation in sepsis and endotoxemia. In monocytes LPS induces the synthesis of tissue factor (TF) which, assembled with factor VII, initiates the blood coagulation cascades. In this study we investigated the mechanism of LPS recognition by monocytes, and the consequent expression of TF mRNA and TF activity. We also studied the inhibition of these effects of LPS by rBPI23, a 23-kD recombinant fragment of bactericidal/permeability increasing protein, which has been shown to antagonize LPS in vitro and in vivo. Human peripheral blood mononuclear cells, or monocytes isolated by adherence, were stimulated with Escherichia coli O113 LPS at physiologically relevant concentrations (> or = 10 pg/mL). The effect of LPS was dependent on the presence of the serum protein LBP (lipopolysaccharide-binding protein), as shown by the potentiating effect of human recombinant LBP or serum. Furthermore, recognition of low amounts of LPS by monocytes was also dependent on CD14 receptors, because monoclonal antibodies against CD14 greatly reduced the LPS sensitivity of monocytes in the presence of serum or rLBP. Induction of TF activity and mRNA expression by LPS were inhibited by rBPI23. The expression of tumor necrosis factor showed qualitatively similar changes. Considering the involvement of LPS-induced TF in the potentially lethal intravascular coagulation in sepsis, inhibition of TF induction by rBPI23 may be of therapeutic benefit.

scholarly journals Cloning of mouse ptx3, a new member of the pentraxin gene family expressed at extrahepatic sites

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1862-1872 ◽  
Author(s):  
M Introna ◽  
VV Alles ◽  
M Castellano ◽  
G Picardi ◽  
L De Gioia ◽  
...  
Keyword(s):  
Gene Family ◽  
Tertiary Structure ◽  
Helical Structure ◽  
Distinct Pattern ◽  
Mononuclear Phagocytes ◽  
Acute Phase Reactants ◽  
Inflammatory Reactions ◽  
Reactive Protein

Abstract Pentraxins, which include C reactive protein (CRP) and serum amyloid P component (SAP), are prototypic acute phase reactants that serve as indicators of inflammatory reactions. Here we report genomic and cDNA cloning of mouse ptx3 (mptx3), a member of the pentraxin gene family and characterize its extrahepatic expression in vitro and in vivo. mptx3 is organized into three exons on chromosome 3: the first (43 aa) and second exon (175 aa) code for the signal peptide and for a protein portion with no high similarity to known sequences the third (203 aa) for a domain related to classical pentraxins, which contains the “pentraxin family signature.” Analysis of the N terminal portion predicts a predominantly alpha helical structure, while the pentraxin domain of ptx3 is accommodated comfortably in the tertiary structure fold of SAP. Normal and transformed fibroblasts, undifferentiated and differentiated myoblasts, normal endothelial cells, and mononuclear phagocytes express mptx3 mRNA and release the protein in vitro on exposure to interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF)alpha. mptx3 was induced by bacterial lipopolysaccharide in vivo in a variety of organs and, most strongly, in the vascular endothelium of skeletal muscle and heart. Thus, mptx3 shows a distinct pattern of in vivo expression indicative of a significant role in cardiovascular and inflammatory pathology.

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