Polyinosinic-polycytidylic acid has therapeutic effects against cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via TLR3

• Published in: The Journal of immunology (1950) 2014-05, Vol.192 (10), p.4783-4794
• Main Authors: Wang, Peng-Fei, Fang, Huang, Chen, Jing, Lin, Sen, Liu, Yong, Xiong, Xiao-Yi, Wang, Yan-Chun, Xiong, Ren-Ping, Lv, Feng-Lin, Wang, Jian, Yang, Qing-Wu
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - pharmacology; Brain Ischemia - drug therapy; Brain Ischemia - genetics; Brain Ischemia - immunology; Brain Ischemia - pathology; Down-Regulation - drug effects; Down-Regulation - genetics; Down-Regulation - immunology; HSP27 Heat-Shock Proteins - genetics; HSP27 Heat-Shock Proteins - immunology; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - immunology; Innate Immunity and Inflammation; Interleukin-1beta - genetics; Interleukin-1beta - immunology; Male; Mice; Mice, Knockout; Poly I-C - pharmacology; Rats; Rats, Sprague-Dawley; Reperfusion Injury - drug therapy; Reperfusion Injury - genetics; Reperfusion Injury - immunology; Reperfusion Injury - pathology; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - immunology; Time Factors; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 3 - immunology; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1303108

Recent reports have shown that preconditioning with the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) protects against cerebral ischemia/reperfusion (I/R) injury. However, it is unclear whether poly(I:C) treatment after cerebral I/R injury is also effective. We used mouse/rat middle cerebral artery occlusion and cell oxygen-glucose deprivation models to evaluate the therapeutic effects and mechanisms of poly(I:C) treatment. Poly(I:C) was i.p. injected 3 h after ischemia (treatment group). Cerebral infarct volumes and brain edemas were significantly reduced, and neurologic scores were significantly increased. TNF-α and IL-1β levels were markedly decreased, whereas IFN-β levels were greatly increased, in the ischemic brain tissues, cerebral spinal fluid, and serum. Injuries to hippocampal neurons and mitochondria were greatly reduced. The numbers of TUNEL-positive and Fluoro-Jade B(+) cells also decreased significantly in the ischemic brain tissues. Poly(I:C) treatment increased the levels of Hsp27, Hsp70, and Bcl2 and decreased the level of Bax in the ischemic brain tissues. Moreover, poly(I:C) treatment attenuated the levels of TNF-α and IL-1β in serum and cerebral spinal fluid of mice stimulated by LPS. However, the protective effects of poly(I:C) against cerebral ischemia were abolished in TLR3(-/-) and TLR4(-/-)mice. Poly(I:C) downregulated TLR4 signaling via TLR3. Poly(I:C) treatment exhibited obvious protective effects 14 d after ischemia and was also effective in the rat permanent middle cerebral artery occlusion model. The results suggest that poly(I:C) exerts therapeutic effects against cerebral I/R injury through the downregulation of TLR4 signaling via TLR3. Poly(I:C) is a promising new drug candidate for the treatment of cerebral infarcts.