Protective responses to sublytic complement in the retinal pigment epithelium
Open accessAbstract
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.
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Lysosomes in the RPE participate in calcium signaling and membrane repair in addition to their degradative functions, and these mechanisms are critical for maintaining RPE health and integrity.
“lysosomes in the RPE perform various roles; in addition to their degradative functions, they participate in calcium signaling and membrane repair - mechanisms that are critical for maintaining RPE health and integrity (Liu et al., 2008; Tan et al., 2016).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Tan et al., 2016
Endosomal defects that manifest as inefficient sorting or recycling can compromise the health of the RPE by making it susceptible to complement attack.
“Endosomal defects that manifest as inefficient sorting or recycling can compromise the health of the RPE by making it susceptible to complement attack (Georgiannakis et al., 2015; Tan et al., 2016).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Tan et al., 2016
In RPE with defective microtubule transport such as in the Abca4−/− mouse, lysosomes are sequestered in the perinuclear region; the resulting decrease in membrane proximal lysosomes prevents membrane repair after complement attack and makes the RPE susceptible to mitochondrial damage.
“In RPE with defective microtubule transport such as in the Abca4−/− mouse, lysosomes are sequestered in the perinuclear region. The resulting decrease in membrane proximal lysosomes prevents membrane repair after complement attack, and makes the RPE susceptible to mitochondrial damage (Tan et al., 2016).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Tan et al., 2016
In normal RPE, complement attack accelerates CD59 recycling to the apical membrane to prevent MAC assembly; in the Abca4−/− mouse model of Stargardt disease, increased cholesterol prevents CD59 recycling and reroutes it to lysosomes, leading to increased MAC formation, increased intracellular calcium, mitochondrial fragmentation, and oxidative stress.
“In normal RPE, complement attack accelerates CD59 recycling to the apical membrane to prevent MAC assembly. However, in the Abca4−/− mouse model of Stargardt disease, increased cholesterol prevents CD59 recycling in response to complement, and reroutes it to lysosomes. The resultant increase in MAC formation leads to increased intracellular calcium, mitochondrial fragmentation, and oxidative”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Tan et al., 2016
Complement attack stimulates peripheral lysosomes in the RPE to undergo rapid exocytosis, which helps eliminate cytotoxic C5b-9 terminal complement complex or MAC pores.
“Live-cell TIRF imaging of polarized primary RPE cultures showed that complement attack stimulates peripheral lysosomes in the RPE to undergo rapid exocytosis, which helps eliminate cytotoxic C5b-9 terminal complement complex or MAC pores (Tan et al., 2016).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Tan et al., 2016
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- Authors
- Tan, L. X., Toops, K. A., & Lakkaraju, A.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Lakkaraju, Aparna
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-07-18
- Volume
- 113
- Issue
- 31
- Pages
- 8789-8794
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4978296
- OpenAlex
- W2478855357
- Cited by
- 66
- References
- 38
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 12 · 2023: 8 · 2022: 5 · 2021: 2 · 2020: 13 · 2019: 5 · 2018: 5 · 2017: 4
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | NIH | National Eye Institute (R01EY023299)
- BrightFocus Foundation (M2015350)
- Research to Prevent Blindness (Unrestricted grant)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- retinal pigment epithelium, complement system, membrane attack complex, lysosome exocytosis, mitochondrial injury, cholesterol accumulation, acid sphingomyelinase, tubulin acetylation, intracellular calcium, macular degeneration, Stargardt disease, ABCA4, oxidative stress, mitochondrial fragmentation, cholesterol efflux
- MeSH terms
- Stargardt Disease, Animals, Calcium, Cells, Cultured, Cholesterol, Complement System Proteins, Humans, Lysosomes, Macular Degeneration, Mitochondria, Sphingomyelin Phosphodiesterase, Swine, Complement Membrane Attack Complex, Mice, Knockout, Oxidative Stress, ATP-Binding Cassette Transporters, CD59 Antigens, Retinal Pigment Epithelium
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