Retinal Pigment Epithelial Cells Mitigate the Effects of Complement Attack by Endocytosis of C5b-9

Georgiannakis, Apostolos; Burgoyne, Thomas; Lueck, Katharina; Futter, Clare E.; Greenwood, John; Moss, Stephen E.

doi:10.4049/jimmunol.1500937

Cited by 33 publications

(33 citation statements)

References 73 publications

(63 reference statements)

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“…MAC activation on choroidal endothelial cells induces lysis (Zeng et al, 2016), but studies describe how RPE cells are resistant to MAC-mediated lysis, and efficiently remove MAC before lysis can take place; instead, sub-lytic MAC induces inflammatory signaling pathway activation (Lueck et al, 2011;Kunchithapautham and Rohrer, 2011;Georgiannakis et al, 2015). In support of these reports, we did not observe RPE cell death under TLR2-induced MAC-forming culture conditions in vitro, indicating that TLR2-induced MAC formation on RPE cells is sub-lytic.…”

Section: Discussionsupporting

confidence: 80%

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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Section: Discussionsupporting

confidence: 80%

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

et al. 2020

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“…Endocytosis and lysosomal degradation of MACs by the RPE (11) and shedding of MACs into the extracellular medium (36) have been reported after tens of minutes or hours of exposure to complement; whether these mechanisms also occur over faster timescales remains to be determined. Data presented here and in other studies (11) show that defects in any of these mechanisms converge on a common pathway of mitochondrial damage in the RPE.…”

Section: Discussionsupporting

confidence: 75%

“…Polarized RPE were exposed to either 10% NHS or 60 μg/mL purified C9 reconstituted in 10% C9-depleted serum (Quidel) for 10 min (11,12). Heat-inactivated NHS (56°C for 30 min) and C9-depleted sera were used as negative controls.…”

Section: Methodsmentioning

confidence: 99%

“…Exposure to MACs over 12-24 h causes mitochondrial stress due to persistent increase in [Ca 2+ ] i (11,24). Here, we asked whether defective lysosome exocytosis leads to mitochondrial damage in the RPE after a short exposure to complement.…”

Section: Defective Lysosome Exocytosis Promotes Mitochondrial Damage mentioning

confidence: 99%

“…The complement cascade is activated by insults that disturb RPE homeostasis, including defective clearance of phagocytosed photoreceptor outer segments (6) and abnormal accumulation of vitamin A dimers (7-9) or oxidized lipids (10) in the RPE. Studies also show that exposure to sublytic levels of MAC alters RPE barrier integrity, causes mitochondrial stress, and induces secretion of VEGF and proinflammatory cytokines (11,12). Thus, RPE dysfunction activates the complement cascade, which can promote further RPE damage and establish a vicious cycle of chronic inflammation within the retina (13).…”

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confidence: 99%

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Protective responses to sublytic complement in the retinal pigment epithelium

Tan

Toops

Lakkaraju

2016

Proc. Natl. Acad. Sci. U.S.A.

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The retinal pigment epithelium (RPE) is a key site of injury in inherited and age-related macular degenerations. Abnormal activation of the complement system is a feature of these blinding diseases, yet how the RPE combats complement attack is poorly understood. The complement cascade terminates in the cell-surface assembly of membrane attack complexes (MACs), which promote inflammation by causing aberrant signal transduction. Here, we investigated mechanisms crucial for limiting MAC assembly and preserving cellular integrity in the RPE and asked how these are compromised in models of macular degeneration. Using polarized primary RPE and the pigmented Abca4 −/− Stargardt disease mouse model, we provide evidence for two protective responses occurring within minutes of complement attack, which are essential for maintaining mitochondrial health in the RPE. First, accelerated recycling of the membrane-bound complement regulator CD59 to the RPE cell surface inhibits MAC formation. Second, fusion of lysosomes with the RPE plasma membrane immediately after complement attack limits sustained elevations in intracellular calcium and prevents mitochondrial injury. Cholesterol accumulation in the RPE, induced by vitamin A dimers or oxidized LDL, inhibits these defense mechanisms by activating acid sphingomyelinase (ASMase), which increases tubulin acetylation and derails organelle traffic. Defective CD59 recycling and lysosome exocytosis after complement attack lead to mitochondrial fragmentation and oxidative stress in the RPE. Drugs that stimulate cholesterol efflux or inhibit ASMase restore both these critical safeguards in the RPE and avert complement-induced mitochondrial injury in vitro and in Abca4 −/− mice, indicating that they could be effective therapeutic approaches for macular degenerations.he complement system is an important regulator of immunity and inflammation. Complement activation by the classical, alternative, or lectin pathways results in the assembly of C5b-9 membrane attack complexes (MACs), which form membrane pores and cause target cell lysis. Within the eye, a low level of constant complement activity is necessary for immune surveillance, and several membrane-bound and soluble regulators prevent excessive complement activation (1). An imbalance between complement activation and inhibition in the retina is implicated in the pathogenesis of age-related macular degeneration (AMD), which causes central vision loss in more than 30 million people globally (reviewed in refs. 2-4).Evidence suggests that the retinal pigment epithelium (RPE), which helps maintain ocular immune privilege, is the first line of defense against unregulated complement activation in the retina (5). The complement cascade is activated by insults that disturb RPE homeostasis, including defective clearance of phagocytosed photoreceptor outer segments (6) and abnormal accumulation of vitamin A dimers (7-9) or oxidized lipids (10) in the RPE. Studies also show that exposure to sublytic levels of MAC alters RPE barrier integrity, causes...

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Complement modulation reverses pathology in Y402H-retinal pigment epithelium cell model of age-related macular degeneration by restoring lysosomal function

Cerniauskas

Kurzawa‐Akanbi

Xie

et al. 2020

Stem Cells Translational Medicine

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Age-related macular degeneration (AMD) is a multifactorial disease, which is characterized by loss of central vision, affecting one in three people by the age of 75. The Y402H polymorphism in the complement factor H (CFH) gene significantly increases the risk of AMD. We show that Y402H-AMD-patient-specific retinal pigment epithelium (RPE) cells are characterized by a significant reduction in the number of melanosomes, an increased number of swollen lysosome-like-vesicles with fragile membranes, Cathepsin D leakage into drusen-like deposits and reduced lysosomal function. The turnover of C3 is increased significantly in high-risk RPE cells, resulting in higher internalization and deposition of the Terminal Complement Complex C5b-9 at the lysosomes. Inhibition of C3 processing via the compstatin analogue Cp40 reverses the disease phenotypes by relieving the lysosomes of their overburden and restoring their function. These findings suggest that modulation of the complement system represents a useful therapeutic approach for AMD patients associated with complement dysregulation.

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Retinal Pigment Epithelial Cells Mitigate the Effects of Complement Attack by Endocytosis of C5b-9

Cited by 33 publications

References 73 publications

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

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

Protective responses to sublytic complement in the retinal pigment epithelium

Complement modulation reverses pathology in Y402H-retinal pigment epithelium cell model of age-related macular degeneration by restoring lysosomal function

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