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M. K. Ko, S. Saraswathy, J. G. Parikh, G.-S. Wu, N. A. Rao; Toll-Like Receptor 4 in the Retinal Microglia Leads to Photoreceptor Oxidative Stress. Invest. Ophthalmol. Vis. Sci. 2009;50(13):6257.
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© ARVO (1962-2015); The Authors (2016-present)
Toll like receptors (TLRs) are key components of an innate immune response. We previously found subcutaneously injected complete Freund's adjuvant (CFA) alone induced expression of TLRs in the retina. Herein, we investigated whether CFA-mediated TLR activation causes retinal oxidative stress.
Expression of TLRs and their pathway genes was determined by PCR array, qPCR, and immunohistochemistry in B10RIII mice injected with a) CFA + antigen (IRBP); b) CFA only; c) incomplete Freund’s adjuvant ; and d) untreated mice at day 5 post injection (p.i.). Retina, liver, and brain tissues were analyzed. Rag1-/- mice were used to determine whether adaptive immunity was involved in induction of TLRs and oxidative stress.
TLRs (1, 4, 6, and 9) and relative genes for innate immune response, including Map kinases, TLR adaptor, NFΚB, and TNF/TNF receptor family, were upregulated in retinas of CFA- vs non-injected animals. No significant difference was seen in gene regulation in mice injected with CFA or CFA+IRBP nor was there any inflammation in retina, choroid or anterior uvea of CFA-injected animals on day 5 p.i. Bacterial DNA was detected in retina by qPCR, including other tissues. In non-injected control retinas, the CD11b+ microglia were detected in the inner plexiform layer with no expression of TLR1, 4, 6 and 9, and MHC class II. In CFA-injected retina, primarily TLR4 was found, co-localized with CD11b+ and MHCII+ microglia. In the retina of Rag1-/- mice, TLR4+ microglial cells were seen near the inner nuclear layer, similar to wild type controls. 8-OHdG, a marker for oxidative DNA damage, was immunolocalized to inner segments of photoreceptors and inner nuclear layers, similar to the wild type controls.
TLR4 is expressed and localized in retinal microglia in innate immune response. TLR expression is correlated with detection of mycobaterial DNA in the retina. TLR4-mediated innate immune response and cytokines, especially TNF, in the retinal microglia results in oxidative stress phenomenon, independent of adaptive immune response.
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