New Insights on Complement Inhibitor CD59 in Mouse Laser-Induced Choroidal Neovascularization: Mislocalization After Injury and Targeted Delivery for Protein Replacement

Schnabolk, Gloriane; Beon, M; Tomlinson, Stephen; Rohrer, Bärbel

doi:10.1089/jop.2016.0101

Cited by 7 publications

(5 citation statements)

References 49 publications

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“…Inhibiting all the pathways of complement activation via CR2-Crry treatment is not the best option for reducing complement-related ischemic brain injury because it affects the subsequent tissue regeneration after ischemic stroke. The role of CR2-CD59 has been reported in a mouse model of choroidal neovascularization (CNV), where it contributes to emolliating the severity of choroidal neovascularization [144]. However, the effectiveness of CR2-CD59 treatment for ischemic stroke has not yet been clarified.…”

Section: Complement In Ischemic Strokementioning

confidence: 99%

Significance of Complement System in Ischemic Stroke: A Comprehensive Review

Liu

Zhang

et al. 2019

Aging and disease

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The complement system is an essential part of innate immunity, typically conferring protection via eliminating pathogens and accumulating debris. However, the defensive function of the complement system can exacerbate immune, inflammatory, and degenerative responses in various pathological conditions. Cumulative evidence indicates that the complement system plays a critical role in the pathogenesis of ischemic brain injury, as the depletion of certain complement components or the inhibition of complement activation could reduce ischemic brain injury. Although multiple candidates modulating or inhibiting complement activation show massive potential for the treatment of ischemic stroke, the clinical availability of complement inhibitors remains limited. The complement system is also involved in neural plasticity and neurogenesis during cerebral ischemia. Thus, unexpected side effects could be induced if the systemic complement system is inhibited. In this review, we highlighted the recent concepts and discoveries of the roles of different kinds of complement components, such as C3a, C5a, and their receptors, in both normal brain physiology and the pathophysiology of brain ischemia. In addition, we comprehensively reviewed the current development of complement-targeted therapy for ischemic stroke and discussed the challenges of bringing these therapies into the clinic. The design of future experiments was also discussed to better characterize the role of complement in both tissue injury and recovery after cerebral ischemia. More studies are needed to elucidate the molecular and cellular mechanisms of how complement components exert their functions in different stages of ischemic stroke to optimize the intervention of targeting the complement system.

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Section: Complement In Ischemic Strokementioning

confidence: 99%

Significance of Complement System in Ischemic Stroke: A Comprehensive Review

Liu

Zhang

et al. 2019

Aging and disease

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“…Inhibition of MAC using the murine complement inhibitor CR2-CD59 to inhibit MAC assembly reduced ocular injury severity. 87 Anti-C5 Therapy Anti-C5 antibody binds to C5, preventing cleavage into C5a, the anaphylatoxin, and C5b, a terminal complement component, and thus, inhibiting MAC formation. Anti-C5 monoclonal antibody (eculizumab) was approved for treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.…”

Section: Mac In Other Diseasesmentioning

confidence: 99%

Complement Membrane Attack Complex

Xie

Jane‐wit

Pober

2020

The American Journal of Pathology

128

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The complement membrane attack complex (MAC) is classically known as a cytolytic effector of innate and adaptive immunity that forms pores in the plasma membrane of pathogens or targeted cells, leading to osmolysis. Nucleated cells resist MAC-mediated cytolysis by expression of inhibitors that block MAC assembly or by rapid removal of MAC through endocytosis or shedding. In the absence of lysis, MAC may induce intracellular signaling and cell activation, responses implicated in a variety of autoimmune, inflammatory, and transplant disease settings. New discoveries into the structure and biophysical properties of MAC revealed heterogeneous MAC precursors and conformations that provide insights into MAC function. In addition, new mechanisms of MAC-mediated signaling and its contribution to disease pathogenesis have recently come to light. MAC-activated cells have been found to express proinflammatory proteinsdoften through NF-kBedependent transcription, assemble inflammasomes, enabling processing, and facilitate secretion of IL-1b and IL-18, as well as other signaling pathways. These recent insights into the mechanisms of action of MAC provide an updated framework to therapeutic approaches that can target MAC assembly, signaling, and proinflammatory effects in various complement-mediated diseases.

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“…The laser-induced CNV model is widely used as model of AMD with pathological angiogenegsis 22,23 . Two days after argon laser-induced injury of Bruch’s membrane, mouse eyes were dissected and the choroidal tissues associating with RPE were isolated.…”

Section: Resultsmentioning

confidence: 99%

Activator of G-protein signaling 8 is involved in VEGF-induced choroidal neovascularization

Hayashi

Mamun

Takeyama

et al. 2019

Sci Rep

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Choroidal neovascularization (CNV) is associated with age-related macular degeneration (AMD), a major cause of vision loss among elderly people. Vascular endothelial cell growth factor (VEGF) is essential for the development and progression of AMD, and VEGF signaling molecules are effective targets for the treatment of AMD. We recently reported that activator of G-protein signaling 8 (AGS8), a receptor-independent Gβγ regulator, is involved in VEGF-induced angiogenesis in cultured endothelial cells (EC); however, the role of AGS8 in CNV is not yet understood. This study aimed to explore the role of AGS8 in CNV in cultured cells, explanted choroid tissue, and laser-induced CNV in a mouse AMD model. AGS8 knockdown in cultured choroidal EC inhibited VEGF-induced VEGFR-2 phosphorylation, cell proliferation, and migration. AGS8 knockdown also downregulated cell sprouting from mouse choroidal tissue in ex vivo culture. A mouse model of laser-induced CNV, created to analyze the roles of AGS8 in vivo, demonstrated that AGS8 mRNA was significantly upregulated in choroidal lesions and AGS8 was specifically expressed in the neovasculature. Local AGS8 knockdown in intravitreal tissue significantly inhibited laser-induced AGS8 upregulation and suppressed CNV, suggesting that AGS8 knockdown in the choroid has therapeutic potential for AMD. Together, these results demonstrate that AGS8 plays critical roles in VEGF-induced CNV.

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New Insights on Complement Inhibitor CD59 in Mouse Laser-Induced Choroidal Neovascularization: Mislocalization After Injury and Targeted Delivery for Protein Replacement

Abstract: These data further support the importance of CD59 in controlling ocular injury responses and indicate that pharmacological inhibition of the MAC with CR2-CD59 may be a viable therapeutic approach for reducing complement-mediated ocular pathology.

Cited by 7 publications

References 49 publications

Significance of Complement System in Ischemic Stroke: A Comprehensive Review

Significance of Complement System in Ischemic Stroke: A Comprehensive Review

Complement Membrane Attack Complex

Activator of G-protein signaling 8 is involved in VEGF-induced choroidal neovascularization

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