Toll-like receptor 4 mediates retinal ischemia/reperfusion injury through nuclear factor-κB and spleen tyrosine kinase activation. 2013

Fumiya Ishizuka, and Masamitsu Shimazawa, and Yuki Inoue, and Yusuke Nakano, and Hiromi Ogishima, and Shinsuke Nakamura, and Kazuhiro Tsuruma, and Hiroyuki Tanaka, and Naoki Inagaki, and Hideaki Hara
Molecular Pharmacology and Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.

OBJECTIVE Inflammatory response has a critical role in neuronal damage after retinal ischemia-reperfusion (I/R) injury, and is regulated tightly by the toll-like receptor (TLR) 4. This study aimed to determine whether TLR4 is involved with injury in an ocular ischemic syndrome mice model and to clarify the downstream pathway of TLR4. METHODS To cause retinal ischemia, we ligated the unilateral external carotid artery and the pterygopalatine artery of mice for 5 hours. Five days after reperfusion, retinal histologic analysis was performed. To examine the downstream pathway of TLR4, we analyzed the changes in phosphorylation of nuclear factor-κB (NF-κB) by Western blotting. In addition, we evaluated the expression of phosphorylated spleen tyrosine kinase (Syk), which is an adaptor protein of TLR4, and the effects of a Syk inhibitor (piceatannol) against the retinal ischemic damage and TLR4 signaling. RESULTS TLR4 knock-out (KO) mice significantly inhibited the histologic damage induced by I/R compared to wild-type mice. The expression of TLR4 was upregulated after I/R in wild-type mice. The phosphorylation level of NF-κB after I/R in TLR4 KO mice was decreased compared to that in wild-type mice. The phosphorylated Syk expression was upregulated after I/R, and the upregulation was inhibited in TLR4 KO mice. Piceatannol inhibited the histologic and functional retinal damage, and reduced the phosphorylation level of NF-κB induced by I/R. CONCLUSIONS These data indicate that TLR4 has a pivotal role in the pathogenesis of ocular ischemic syndrome, and Syk and NF-κB are key molecules in TLR4 signaling in retinal ischemia.

UI MeSH Term Description Entries
D011505 Protein-Tyrosine Kinases Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors. Tyrosine Protein Kinase,Tyrosine-Specific Protein Kinase,Protein-Tyrosine Kinase,Tyrosine Kinase,Tyrosine Protein Kinases,Tyrosine-Specific Protein Kinases,Tyrosylprotein Kinase,Kinase, Protein-Tyrosine,Kinase, Tyrosine,Kinase, Tyrosine Protein,Kinase, Tyrosine-Specific Protein,Kinase, Tyrosylprotein,Kinases, Protein-Tyrosine,Kinases, Tyrosine Protein,Kinases, Tyrosine-Specific Protein,Protein Kinase, Tyrosine-Specific,Protein Kinases, Tyrosine,Protein Kinases, Tyrosine-Specific,Protein Tyrosine Kinase,Protein Tyrosine Kinases,Tyrosine Specific Protein Kinase,Tyrosine Specific Protein Kinases
D012164 Retinal Diseases Diseases involving the RETINA. Disease, Retinal,Diseases, Retinal,Retinal Disease
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004596 Electroretinography Recording of electric potentials in the retina after stimulation by light. Electroretinographies
D000072377 Syk Kinase An SH2 domain-containing non-receptor tyrosine kinase that regulates signal transduction downstream of a variety of receptors including B-CELL ANTIGEN RECEPTORS. It functions in both INNATE IMMUNITY and ADAPTIVE IMMUNITY and also mediates signaling in CELL ADHESION; OSTEOGENESIS; PLATELET ACTIVATION; and vascular development. SYK Tyrosine Kinase,Spleen Tyrosine Kinase,Kinase, SYK Tyrosine,Kinase, Spleen Tyrosine,Kinase, Syk,Tyrosine Kinase, SYK,Tyrosine Kinase, Spleen
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015153 Blotting, Western Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes. Immunoblotting, Western,Western Blotting,Western Immunoblotting,Blot, Western,Immunoblot, Western,Western Blot,Western Immunoblot,Blots, Western,Blottings, Western,Immunoblots, Western,Immunoblottings, Western,Western Blots,Western Blottings,Western Immunoblots,Western Immunoblottings
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D015427 Reperfusion Injury Adverse functional, metabolic, or structural changes in tissues that result from the restoration of blood flow to the tissue (REPERFUSION) following ISCHEMIA. Ischemia-Reperfusion Injury,Injury, Ischemia-Reperfusion,Injury, Reperfusion,Reperfusion Damage,Damage, Reperfusion,Injury, Ischemia Reperfusion,Ischemia Reperfusion Injury,Ischemia-Reperfusion Injuries,Reperfusion Damages,Reperfusion Injuries
D016328 NF-kappa B Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two DNA-binding subunits: NF-kappa B1 and relA. Immunoglobulin Enhancer-Binding Protein,NF-kappa B Complex,Nuclear Factor kappa B,Transcription Factor NF-kB,kappa B Enhancer Binding Protein,Ig-EBP-1,NF-kB,NF-kappaB,Nuclear Factor-Kappab,Complex, NF-kappa B,Enhancer-Binding Protein, Immunoglobulin,Factor NF-kB, Transcription,Factor-Kappab, Nuclear,Ig EBP 1,Immunoglobulin Enhancer Binding Protein,NF kB,NF kappa B Complex,NF kappaB,NF-kB, Transcription Factor,Nuclear Factor Kappab,Transcription Factor NF kB

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