| First Author | Ko MK | Year | 2011 |
| Journal | Invest Ophthalmol Vis Sci | Volume | 52 |
| Issue | 8 | Pages | 5824-35 |
| PubMed ID | 21666244 | Mgi Jnum | J:181405 |
| Mgi Id | MGI:5311278 | Doi | 10.1167/iovs.10-6357 |
| Citation | Ko MK, et al. (2011) The role of TLR4 activation in photoreceptor mitochondrial oxidative stress. Invest Ophthalmol Vis Sci 52(8):5824-35 |
| abstractText | PURPOSE: 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. METHODS: 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]-alpha(KO), or caspase 7(KO) 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. RESULTS: 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-alpha(KO) mice. CFA-mediated inducible nitric oxide synthase expression in the retina was significantly decreased in TNF-alpha(KO) mice. CONCLUSIONS: Retinal photoreceptors are susceptible to mitochondrial oxidative stress/mtDNA damage in robust TLR4-mediated innate immune response. |
