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MinHee K. Ko, Sindhu Saraswathy, Jignesh G. Parikh, Narsing A. Rao; The Role of TLR4 Activation in Photoreceptor Mitochondrial Oxidative Stress. Invest. Ophthalmol. Vis. Sci. 2011;52(8):5824-5835. doi: 10.1167/iovs.10-6357.
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Herein the authors investigated whether the activation of Toll-like receptors (TLRs) in the innate immune response causes retinal photoreceptor oxidative stress and mitochondrial DNA (mtDNA) damage.
On day 5 after injection of complete Freund's adjuvant containing heat-killed Mycobacterium tuberculosis (CFA), retinas were submitted to polymerase chain reaction (PCR) array focused on the TLR signaling, or apoptosis, pathway. CFA-mediated TLR4 activation, oxidative stress, and mtDNA damage were determined in B10.RIII and knockout (KO) mice (recombination activation gene [Rag] 1 KO, TLR4 KO, myeloid differentiation primary response gene 88 [MyD88]KO, tumor necrosis factor [TNF]-αKO, or caspase 7KO mice) using quantitative real-time PCR, enzyme-linked immunosorbent assay, Western blot analysis, and immunohistochemistry. The mycobacterial DNA load on the retina, brain, liver, and spleen was determined by real-time PCR after intracardiac perfusion.
PCR array demonstrated the upregulation of TLRs and their signaling molecules in retinas of CFA-injected mice compared with those of control animals without inflammatory cell infiltration in the retina and uvea. Mycobacterial DNA was detected in the retinas of CFA-injected mice. Retinas of CFA-injected animals showed oxidative stress and mtDNA damage, primarily in the photoreceptor inner segments. Upregulated TLR4 was localized with CD11b+MHCII+ cells but not with GFAP+ astrocytes. This oxidative stress/damage was similar in CFA-injected Rag1 KO mice compared with wild-type controls. Such damage was absent in the retinas of CFA-injected TLR4 KO, MyD88 KO, and TNF-αKO mice. CFA-mediated inducible nitric oxide synthase expression in the retina was significantly decreased in TNF-αKO mice.
Retinal photoreceptors are susceptible to mitochondrial oxidative stress/mtDNA damage in robust TLR4-mediated innate immune response.
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