Connecting the innate and adaptive immune responses in mouse choroidal neovascularization via the anaphylatoxin C5a and γδT-cells
Open accessAbstract
Neovascular age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV). An overactive complement system is associated with AMD pathogenesis, and serum pro-inflammatory cytokines, including IL-17, are elevated in AMD patients. IL-17 is produced by complement C5a-receptor-expressing T-cells. In murine CNV, infiltrating γδT- rather than Th17-cells produce the IL-17 measurable in lesioned eyes. Here we asked whether C5a generated locally in response to CNV recruits IL-17-producing T-cells to the eye. CNV lesions were generated using laser photocoagulation and quantified by imaging; T-lymphocytes were characterized by QRT-PCR. CNV resulted in an increase in splenic IL-17-producing γδT- and Th17-cells; yet in the CNV eye, only elevated levels of γδT-cells were observed. Systemic administration of anti-C5- or anti-C5a-blocking antibodies blunted the CNV-induced production of splenic Th17- and γδT-cells, reduced CNV size and eliminated ocular γδT-cell infiltration. In ARPE-19 cell monolayers, IL-17 triggered a pro-inflammatory state; and splenocyte proliferation was elevated in response to ocular proteins. Thus, we demonstrated that CNV lesions trigger a systemic immune response, augmenting local ocular inflammation via the infiltration of IL-17-producing γδT-cells, which are presumably recruited to the eye in a C5a-dependent manner. Understanding the complexity of complement-mediated pathological mechanisms will aid in the development of an AMD treatment.
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In the choriocapillaris, C5a upregulates the expression of leukocyte adhesion molecules on endothelial cells and plays a key role in recruiting γδ T-cells.
“Furthermore, in the choriocapillaris, C5a upregulates the expression of leukocyte adhesion molecules on endothelial cells [109] and plays a key role in recruiting γδ T-cells [194]”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [194]
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The Role of Inflammation in Age-Related Macular Degeneration
Tan, W., Zou, J., Yoshida, S., Jiang, B., & Zhou, Y. (2020) · International Journal of Biological Sciences · doi:10.7150/ijbs.49890 · Cited by 311 · see citing works
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- Authors
- Coughlin, B., Schnabolk, G., Joseph, K., Raikwar, H., Kunchithapautham, K., Johnson, K., Moore, K., Wang, Y., & Rohrer, B.
- Affiliations
- Medical University of South Carolina (US)
- Ralph H. Johnson VA Medical Center (US)
- Alexion Pharmaceuticals (United States) (US)
- Corresponding author
- Rohrer, Bärbel
- Venue
- Scientific Reports
- Published
- 2016-03-31
- Volume
- 6
- Issue
- 1
- Pages
- 23794-23794
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4814842
- OpenAlex
- W2322911088
- Cited by
- 65
- References
- 86
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 8 · 2023: 9 · 2022: 4 · 2021: 3 · 2020: 9 · 2019: 7 · 2018: 7 · 2017: 7 · 2016: 3
- FWCI
- 8.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX003050, I01 RX000444, RX000444, C06 RR015455)
- Research to Prevent Blindness
- Alexion Pharmaceuticals
- Medical University of South Carolina (C06 RR015455)
- National Institutes of Health (1c06rr015455-01a1)
- National Eye Institute (R01EY019320, R01EY024581)
- National Center for Research Resources (C06 RR-015455)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Keywords
- choroidal neovascularization, neovascular age-related macular degeneration, C5a, anaphylatoxins, γδ T cells, Th17 cells, IL-17, innate-adaptive immune crosstalk, ocular inflammation, ARPE-19 cells, laser photocoagulation
- MeSH terms
- Animals, Cell Line, Cell Movement, Choroid, Humans, Immunity, Innate, Injections, Intravenous, Light Coagulation, Mice, Inbred C57BL, Spleen, Gene Expression, Complement C5a, Receptors, Antigen, T-Cell, gamma-delta, CD8-Positive T-Lymphocytes, Choroidal Neovascularization, Interleukin-17, Receptor, Anaphylatoxin C5a, Mice, Retinal Pigment Epithelium, Adaptive Immunity, Antibodies, Neutralizing, Th17 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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