scholarly journals Hypoxic Processes Induce Complement Activation via Classical Pathway in Porcine Neuroretinas

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3575
Author(s):  
Ana M. Mueller-Buehl ◽  
Torsten Buehner ◽  
Christiane Pfarrer ◽  
Leonie Deppe ◽  
Laura Peters ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Immune System ◽  
Complement System ◽  
Ganglion Cells ◽  
Age Related Macular Degeneration ◽  
Classical Pathway ◽  
Retinal Diseases ◽  
Multifactorial Diseases ◽  
Age Related ◽  
The Complement System

Considering the fact that many retinal diseases are yet to be cured, the pathomechanisms of these multifactorial diseases need to be investigated in more detail. Among others, oxidative stress and hypoxia are pathomechanisms that take place in retinal diseases, such as glaucoma, age-related macular degeneration, or diabetic retinopathy. In consideration of these diseases, it is also evidenced that the immune system, including the complement system and its activation, plays an important role. Suitable models to investigate neuroretinal diseases are organ cultures of porcine retina. Based on an established model, the role of the complement system was studied after the induction of oxidative stress or hypoxia. Both stressors led to a loss of retinal ganglion cells (RGCs) accompanied by apoptosis. Hypoxia activated the complement system as noted by higher C3+ and MAC+ cell numbers. In this model, activation of the complement cascade occurred via the classical pathway and the number of C1q+ microglia was increased. In oxidative stressed retinas, the complement system had no consideration, but strong inflammation took place, with elevated TNF, IL6, and IL8 mRNA expression levels. Together, this study shows that hypoxia and oxidative stress induce different mechanisms in the porcine retina inducing either the immune response or an inflammation. Our findings support the thesis that the immune system is involved in the development of retinal diseases. Furthermore, this study is evidence that both approaches seem suitable models to investigate undergoing pathomechanisms of several neuroretinal diseases.

scholarly journals Interactions between Apolipoprotein E Metabolism and Retinal Inflammation in Age-Related Macular Degeneration

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 635
Author(s):  
Monica L. Hu ◽  
Joel Quinn ◽  
Kanmin Xue
Keyword(s):  
Risk Factor ◽  
Apolipoprotein E ◽  
Macular Degeneration ◽  
Amyloid Beta ◽  
Complement System ◽  
Genetic Risk ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Retinal Inflammation ◽  
The Complement System

Age-related macular degeneration (AMD) is a multifactorial retinal disorder that is a major global cause of severe visual impairment. The development of an effective therapy to treat geographic atrophy, the predominant form of AMD, remains elusive due to the incomplete understanding of its pathogenesis. Central to AMD diagnosis and pathology are the hallmark lipid and proteinaceous deposits, drusen and reticular pseudodrusen, that accumulate in the subretinal pigment epithelium and subretinal spaces, respectively. Age-related changes and environmental stressors, such as smoking and a high-fat diet, are believed to interact with the many genetic risk variants that have been identified in several major biochemical pathways, including lipoprotein metabolism and the complement system. The APOE gene, encoding apolipoprotein E (APOE), is a major genetic risk factor for AMD, with the APOE2 allele conferring increased risk and APOE4 conferring reduced risk, in comparison to the wildtype APOE3. Paradoxically, APOE4 is the main genetic risk factor in Alzheimer's disease, a disease with features of neuroinflammation and amyloid-beta deposition in common with AMD. The potential interactions of APOE with the complement system and amyloid-beta are discussed here to shed light on their roles in AMD pathogenesis, including in drusen biogenesis, immune cell activation and recruitment, and retinal inflammation.

scholarly journals Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells

Gene Therapy ◽  
2021 ◽  
Author(s):  
Anna K. Dreismann ◽  
Michelle E. McClements ◽  
Alun R. Barnard ◽  
Elise Orhan ◽  
Jane P. Hughes ◽  
...  
Keyword(s):  
Complement System ◽  
Functional Expression ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Factor I ◽  
Complement Factor I ◽  
Age Related ◽  
The Complement System

AbstractDry age-related macular degeneration (AMD) is characterised by loss of central vision and currently has no approved medical treatment. Dysregulation of the complement system is thought to play an important role in disease pathology and supplementation of Complement Factor I (CFI), a key regulator of the complement system, has the potential to provide a treatment option for AMD. In this study, we demonstrate the generation of AAV constructs carrying the human CFI sequence and expression of CFI in cell lines and in the retina of C57BL/6 J mice. Four codon optimised constructs were compared to the most common human CFI sequence. All constructs expressed CFI protein; however, most codon optimised sequences resulted in significantly reduced CFI secretion compared to the non-optimised CFI sequence. In vivo expression analysis showed that CFI was predominantly expressed in the RPE and photoreceptors. Secreted protein in vitreous humour was demonstrated to be functionally active. The findings presented here have led to the formulation of an AAV-vectored gene therapy product currently being tested in a first-in-human clinical trial in subjects with geographic atrophy secondary to dry AMD (NCT03846193).

scholarly journals Therapeutic effect of Keap1-Nrf2-ARE pathway-related drugs on age-related eye diseases through anti-oxidative stress

2021 ◽  
Vol 14 (8) ◽  
pp. 1260-1273
Author(s):  
Zi-Yan Cai ◽  
◽  
Ke Liu ◽  
Xuan-Chu Duan ◽  
◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vision Loss ◽  
Eye Diseases ◽  
The Body ◽  
Age Related Macular Degeneration ◽  
Therapeutic Effects ◽  
Related Factor ◽  
Classical Pathway ◽  
Age Related ◽  
Important Relationship

Age-related eye diseases, including cataract, glaucoma, diabetic retinopathy (DR), and age-related macular degeneration (AMD), are the leading causes of vision loss in the world. Several studies have shown that the occurrence and development of these diseases have an important relationship with oxidative stress in the eye. The Keap1-Nrf2-ARE pathway is a classical pathway that resists oxidative stress and inflammation in the body. This pathway is also active in the development of age-related eye diseases. A variety of drugs have been shown to treat age-related eye diseases through the Keap1-Nrf2-ARE (Kelch-like ECH-Associating protein 1- nuclear factor erythroid 2 related factor 2-antioxidant response element) pathway. This review describes the role of oxidative stress in the development of age-related eye diseases, the function and regulation of the Keap1-Nrf2-ARE pathway, and the therapeutic effects of drugs associated with this pathway on age-related eye diseases.

scholarly journals Neuroprotective Potential of Ginkgo biloba in Retinal Diseases

Planta Medica ◽  
2019 ◽  
Vol 85 (17) ◽  
pp. 1292-1303 ◽  
Author(s):  
Isabel Martínez-Solís ◽  
Nuria Acero ◽  
Francisco Bosch-Morell ◽  
Encarna Castillo ◽  
María Eugenia González-Rosende ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ginkgo Biloba ◽  
Redox Homeostasis ◽  
Antioxidant Properties ◽  
Retinal Disease ◽  
Age Related Macular Degeneration ◽  
Retinal Diseases ◽  
Age Related ◽  
The Central Nervous System ◽  
Degenerative Processes

AbstractLike other tissues of the central nervous system, the retina is susceptible to damage by oxidative processes that result in several neurodegenerative disease such as age-related macular degeneration, diabetic retinopathy, glaucoma, ischaemic retinal disease, retinal disease produced by light oxidation, and detached retina, among other diseases. The use of antioxidant substances is a solution to some health problems caused by oxidative stress, because they regulate redox homeostasis and reduce oxidative stress. This is important for neurodegeneration linked to oxidation processes. In line with this, Ginkgo biloba is a medicinal plant with excellent antioxidant properties whose effects have been demonstrated in several degenerative processes, including retinal diseases associated with neurodegeneration. This review describes the current literature on the role of ginkgo in retinal diseases associated with neurodegeneration. The information leads to the conclusion that G. biloba extracts might be a good option to improve certain neurodegenerative retinal diseases, but more research is needed to determine the safety and efficacy of G. biloba in these retinal degenerative processes.

Age-related macular degeneration and the complement system

Immunobiology ◽  
2012 ◽  
Vol 217 (2) ◽  
pp. 127-146 ◽  
Author(s):  
S. Khandhadia ◽  
V. Cipriani ◽  
J.R.W. Yates ◽  
A.J. Lotery
Keyword(s):  
Macular Degeneration ◽  
Complement System ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
The Complement System

scholarly journals MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

2017 ◽  
Vol 114 (20) ◽  
pp. E4048-E4056 ◽  
Author(s):  
Saumya Nagar ◽  
Sarah M. Noveral ◽  
Dorit Trudler ◽  
Kevin M. Lopez ◽  
Scott R. McKercher ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Age Related Macular Degeneration ◽  
Mouse Retina ◽  
Nrf2 Pathway ◽  
Multifactorial Diseases ◽  
Downstream Target ◽  
Age Related ◽  
The Face ◽  
Genetic And Environmental Factors

Gaining mechanistic insight into interaction between causative factors of complex multifactorial diseases involving photoreceptor damage might aid in devising effective therapies. Oxidative stress is one of the potential unifying mechanisms for interplay between genetic and environmental factors that contribute to photoreceptor pathology. Interestingly, the transcription factor myocyte enhancer factor 2d (MEF2D) is known to be important in photoreceptor survival, as knockout of this transcription factor results in loss of photoreceptors in mice. Here, using a mild light-induced retinal degeneration model, we show that the diminished MEF2D transcriptional activity in Mef2d+/− retina is further reduced under photostimulation-induced oxidative stress. Reactive oxygen species cause an aberrant redox modification on MEF2D, consequently inhibiting transcription of its downstream target, nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is a master regulator of phase II antiinflammatory and antioxidant gene expression. In the Mef2d heterozygous mouse retina, NRF2 is not up-regulated to a normal degree in the face of light-induced oxidative stress, contributing to accelerated photoreceptor cell death. Furthermore, to combat this injury, we found that activation of the endogenous NRF2 pathway using proelectrophilic drugs rescues photoreceptors from photo-induced oxidative stress and may therefore represent a viable treatment for oxidative stress-induced photoreceptor degeneration, which is thought to contribute to some forms of retinitis pigmentosa and age-related macular degeneration.

scholarly journals Semi-Quantitative Multiplex Profiling of the Complement System Identifies Associations of Complement Proteins with Genetic Variants and Metabolites in Age-Related Macular Degeneration

2021 ◽  
Vol 11 (12) ◽  
pp. 1256
Author(s):  
I. Erkin Acar ◽  
Esther Willems ◽  
Eveline Kersten ◽  
Jenneke Keizer-Garritsen ◽  
Else Kragt ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Complement System ◽  
Genetic Variants ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Protein ◽  
Complement Proteins ◽  
New Associations ◽  
Age Related ◽  
The Complement System

Age-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world. The complement system has been identified as one of the main AMD disease pathways. We performed a comprehensive expression analysis of 32 complement proteins in plasma samples of 255 AMD patients and 221 control individuals using mass spectrometry-based semi-quantitative multiplex profiling. We detected significant associations of complement protein levels with age, sex and body-mass index (BMI), and potential associations of C-reactive protein, factor H related-2 (FHR-2) and collectin-11 with AMD. In addition, we confirmed previously described associations and identified new associations of AMD variants with complement levels. New associations include increased C4 levels for rs181705462 at the C2/CFB locus, decreased vitronectin (VTN) levels for rs11080055 at the TMEM97/VTN locus and decreased factor I levels for rs10033900 at the CFI locus. Finally, we detected significant associations between AMD-associated metabolites and complement proteins in plasma. The most significant complement-metabolite associations included increased high density lipoprotein (HDL) subparticle levels with decreased C3, factor H (FH) and VTN levels. The results of our study indicate that demographic factors, genetic variants and circulating metabolites are associated with complement protein components. We suggest that these factors should be considered to design personalized treatment approaches and to increase the success of clinical trials targeting the complement system.

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