Toll-Like Receptor 4 Mediates Retinal Ischemia/Reperfusion Injury Through Nuclear Factor-kappa B and Spleen Tyrosine Kinase Activation

作者：Ishizuka Fumiya; Shimazawa Masamitsu; Inoue Yuki; Nakano Yusuke; Ogishima Hiromi; Nakamura Shinsuke; Tsuruma Kazuhiro; Tanaka Hiroyuki; Inagaki Naoki; Hara Hideaki^*

来源：Investigative Ophthalmology & Visual Science, 2013, 54(8): 5807-5816.

DOI：10.1167/iovs.13-11932

• Toll-like receptor 4
• nuclear factor-kappa B
• spleen tyrosine kinase
• piceatannol

PURPOSE. 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-kappa B (NF-kappa B) 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-kappa B 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-kappa B induced by I/R.

• 出版日期2013-8