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Sofia Theodoropoulou, David Copland, Kepeng Ou, Jian Liu, Neal Millar, Andrew D Dick; Interleukin-33 attenuates ocular angiogenesis through a mast cell dependent pathway.. Invest. Ophthalmol. Vis. Sci. 2019;60(9):987.
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Mast cells are ubiquitous resident cells regulating many facets of immune responses including wound healing and tissue remodeling. We have previously shown that IL-33 regulates mast cell metabolism, generating a specific mast cell cytokine signature (IL-4, IL-13) and shows regulation of vascular tight junctions. Our aim in this study was to demonstrate a pivotal role of IL-33 conditioning of mast cells that in turn may regulate angiogenesis and protect vascular barriers and offer potential therapeutic avenue.
Co-cultures of bone marrow derived mast cells (BMMC) and RPE or mouse retinal microvascular endothelial cells (MRMEC) were established. WT and mast cell deficient c-kit-/- mice were employed in the laser-induced CNV model.
Our previous data shows that mast cells (MC) responded directly to RPE-derived and recombinant IL-33 to produce a spectrum of inflammatory cytokines and chemokines in vitro. When we co-culture IL-33 treated MC with MRMECs or RPE both endothelial cultures and RPE monolayer junctions are maintained with increased expression of a whole range of tight junction complex proteins, including afadin, ZO-1 and ZO-2 in MRMECs and RPE. Using an in vitro permeability assay we demonstrated a 40% reduction in vascular leakage from MRMEC monolayer when co-cultured with IL-33 modulated mast cells. Finally furthering our previous demonstration, we have quantified IL-33 induced MC migration into the CNV lesion. Mast cells are present on day 1 in IL-33 treated eyes, whereas mast cells are not observed in CNV lesion before day 3 in control eyes. At the same time CNV formation was significantly attenuated by 65%. Mast cell deficient mice (c-kit-/-), exhibited larger neovascular lesions compared to WT, supporting that absence of mast cells results in pathological wound healing. IL-33 had no effect on CNV formation in c-kit-/- mice.
Our results establish IL-33 as a key cytokine in regulation of ocular neovascular disease and maintenance of outer retinal barrier via a mast cell dependent pathway.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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