Purchase this article with an account.
Sung-Hye Kim, Chengrong Yu, Charles Egwuagu; Characterization of the Role of IRF-8 in the Retina During Autoimmune Uveitis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2503.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Interferon Regulatory Factor (IRF)-8 is required for the development, maturation and expression of anti-microbial defenses of myeloid cells and regulates CFH expression in retinal microglial cells. However, IRF-8-dependent network contains several genes that enhance susceptibility to infection while others confer complete protection against parasitic diseases such as cerebral malaria. We recently showed that retinal cells constitutively express low levels of IRF-8 and its expression increased significantly in the retina during intraocular inflammation. However, the functional significance of IRF-8 expression in retina remains unclear. In this study, we have generated mice with targeted deletion of IRF-8 in the retina to investigate the function of IRF-8 during intraocular inflammation.
We generated two IRF-8 conditional knockout mouse strains by breeding IRF-8 floxed mice (IRF-8 fl/fl) (kind gift from Herbert Morse, NIH) with mice expressing Cre under direction of the α-Cre promoter (α-CRE) or the Rx promoter (Rx). Experimental autoimmune uveitis (EAU) was induced by active immunization with IRBP/CFA. Disease severity was characterized by fundoscopy, optical coherence tomography (OCT), histology and FACS. Visual function was assessed by electroradiography (ERG).
The WT mice developed severe EAU characterized by massive infiltration of inflammatory cells into the retina, photoreceptor cell loss, focal retinitis, retinal vasculitis and multifocal choroiditis, In contrast, the two IRF-8 KO mouse strains developed very mild EAU, suggesting that IRF-8 deletion conferred protection against EAU. However, visual function tests reveal alterations in dark and light adapted ERG in both IRF-8 KO mouse strains.
Our data confirm the pleiotropic effects of IRF-8 in different tissues and suggests that IRF-8 expression may have double-edged effects in the retina. On the one hand, IRF-8 induces transcription of CFH gene and may thus confer protection against age-related macular degeneration (AMD). On the other hand, the reduced inflammation in the IRF-8 KO mice suggest that IRF-8 may promote inflammatory responses in the retina and that therapeutic targeting of IRF-8 may be used to alleviate uveitis.
This PDF is available to Subscribers Only