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R. Mahdi, C.-R. Yu, A. Eseonu, I. Ojini, Y. Lee, X. Liu, A. Amadi-Obi, C. E. Egwuagu; SOCS1 Protects Ocular Tissues From TH17-Mediated Intraocular Inflammation. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2527. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Suppressors of cytokine signaling 1 (SOCS1) protein inhibits activities of proinflammatory cytokines implicated in pathogenic mechanisms of uveitis. SOCS1-deficient (SOCS1KO) mice develop a severe chronic ocular inflammatory disease and its molecular basis is unclear. Because TH17 cells residing in the lamina propria of intestine or skin protect these epithelial tissues from pathogenic bacteria or fungi, while their expansion in the blood by IL-2 leads to inflammatory diseases, we examined whether chronic ocular inflammation in SOCS1KO mice derive from failure to regulate TH17 cells that may reside in ocular epithelial tissues of the cornea or iris.
The SOCS1-/-/STAT1-/- (SOCS1KO) mouse was generated by crossbreeding SOCS+/- and STAT1-/- mouse strains. Eyes, skin, lung, and liver of WT or SOCS1KO mice were examined by histology. RNA and protein isolated from retina, cornea or T-cells were analyzed by Western blotting, RT-PCR, qRT-PCR, intracellular cytokine staining, Gel-shift or ELISA assays.
The SOCS1KO mice develop severe chronic ocular inflammation characterized by orbital cellulites/abscess, corneal ulcers, iritis, vitritis, retinitis and retinal hemorrhage. CD4 cells from SOCS1KO mice preferentially express IL-17, CCR6, CXCR3, while their CD8 cells predominantly express IFN-γ, but not CCR6. Although modest levels of LARC (for CCR6) IP-10, MIG (for CXCR3) are constitutively expressed in the normal mouse cornea, levels of these chemokines are markedly elevated in SOCS1KO eyes. Comparative analysis of signaling pathways of CD4+ T-cells from WT and SOCS1KO mice reveals a hyper-activation of STAT3 in response of knockout cells to IL-23 and IL-6, consistent with expansion of TH17 cells in SOCS1KO mice.
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