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Karis Little, Mei Chen, Heping Xu; Complement C3a Induces Macrophage to Myofibroblast Transition (MMT) in Sub-retinal Fibrosis Secondary to Neovascular Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5552.
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Sub-retinal fibrosis affects around 1 in 3 patients with neovascular Age Related Macular degeneration (nAMD) and can contribute to severe vision loss. The underlying molecular mechanism remains poorly defined. Previously we reported higher levels of C3a in nAMD patients with macular fibrosis. Macrophages can undergo transition into myofibroblast-like cells. This study tested the hypothesis that C3a may contribute to macular fibrosis through induction of Macrophage to Myofibroblast Transition (MMT).
Sub-retinal fibrosis was induced in mice using a protocol described by Jo et al. The existence of MMT was examined by immunohistochemistry. Bone marrow derived macrophages (BMDMs) from C57BL/6J mice were polarized into M2a using 20 ng/ml IL-4. BMDMs were then treated with different concentrations of recombinant C3a (1-10ng/ml) for 48h. Mouse recombinant TGF-β2 (10ng/ml) was used as a control.
Treatment with C3a (10ng/ml) resulted in a small proportion of Naive BMDMs differentiated into α-SMA positive myofibroblast-like cells, and this was also seen in M2a cells. M2a cells were double positive for CD11b and α-SMA, indicative of macrophage-to-myofibroblast transition. The number of cells expressing α-SMA after treatment with 1, 5 and 10ng/ml C3a in M2a cells (65%, 68% and 72%) was increased when compared to M2a BMDMs treated with 10ng/ml TGFβ2 (56%). In addition, F4/80+α-SMA+ cells and F4/80+ C3aR1 +cells were detected in sub-retinal fibrosis lesions in mice.
Our results suggest that macrophages may actively contribute to sub-retinal fibrosis in nAMD through MMT. The C3a/C3aR pathway may play an important role in MMT in macular fibrosis. Targeting this pathway may be a novel approach for the management of macular fibrosis.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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