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Sofia Theodoropoulou, David A Copland, Jian Liu, Jiahui Wu, Andrew D Dick; Interleukin 33 attenuates choroidal neovascularization by activating mast cells.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1627. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
We have reported a protective role of pro-inflammatory cytokine, interleukin 33, in choroidal neovascularization (CNV) formation, by attenuating wound-healing responses. Mast cells are associated with fibrosis and are also known target cells of IL-33, but their role in CNV is not known. Based on our finding that RPE-derived IL-33 could activate bone-marrow-derived mast cells (BMMC), we hypothesized that IL-33 attenuated CNV by activating mast cells.
Upon treatment, RPE cells (ARPE-19 and B6-RPE07) and bone-marrow-derived mast cells (BMMC) were assayed by RT-PCR and Western Blot and ELISA. Choroidal sprouting assay and laser-induced choroidal neovascularization (CNV) were used as models of ocular angiogenesis. RPE-choroid explants were treated with various doses of IL-33 and mast cell inhibitor ACK2 (anti-c-kit antibody), and assayed by ELISA. CNV was induced in WT and ST2-/- mice (C57BL/6) by laser photocoagulation (4 lesions per fundus). IL-33 alone or in combination with ACK2 was administered by intravitreal injection. The development of neovascular lesions was assessed by optical coherence tomography and immunofluorescence 7 days post injection. Mast cells (MC) infiltration was evaluated by immunohistochemistry.
Mast cells expressed high levels of ST2, and responded directly to IL-33 to produce many inflammatory cytokines and chemokines in vitro, when cultured with IL-33 rich RPE supernatant. Ex vivo, IL-33 treatment reduced vascular sprouting in RPE-choroidal explants, but this effect was perturbed when administered with mast cells inhibitor ACK2.In vivo, choroidal MCs that had infiltrated the sites of laser injury and surrounding retina were observed 7 days following laser. Intravitreal IL-33 attenuated CNV formation, and this was accompanied by increased MC infiltration in the neovascular lesions. Conversely, in ST2-/- mice, similar treatment with IL-33 did not affect CNV size or extent of MC infiltration. Intravitreal administration of ACK2 with IL-33 reversed the anti-angiogenic properties of IL-33.
IL-33/ST2 signaling regulates ocular angiogenesis, influencing tissue remodeling via an IL-33-driven, mast-cell-dependent pathway. Collectively, these data distinguishes pathways for subverting AMD pathology.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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