Function and mechanism of toll-like receptors in cerebral ischemic tolerance: from preconditioning to treatment

Journal of Neuroinflammation

Qing-Wu Yang¹  Wei Duan¹  Yan-Chun Wang¹  Jing Chen¹  Xiao-Yi Xiong¹  Peng-Fei Wang² 

[1] Department of Neurology, Xinqiao Hospital & the Second Affiliated Hospital, the Third Military Medical University, No. 183, Xinqiao Main Street, Chongqing 400037, Shapingba District, China;Department of Neurology, Weihai municipal Hospital, Weihai 264200, China

关键词: TLRs signaling;    Toll-like receptors;    Inflammation;    Ischemic tolerance;    Postconditioning;    Preconditioning;   

Others  :  1213716
DOI  :  10.1186/s12974-015-0301-0

 received in 2014-12-02, accepted in 2015-04-13,  发布年份 2015

【 摘 要 】

Increasing evidence suggests that toll-like receptors (TLRs) play an important role in cerebral ischemia-reperfusion injury. The endogenous ligands released from ischemic neurons activate the TLR signaling pathway, resulting in the production of a large number of inflammatory cytokines, thereby causing secondary inflammation damage following cerebral ischemia. However, the preconditioning for minor cerebral ischemia or the preconditioning with TLR ligands can reduce cerebral ischemic injury by regulating the TLR signaling pathway following ischemia in brain tissue (mainly, the inhibition of the TLR4/NF-κB signaling pathway and the enhancement of the interferon regulatory factor-dependent signaling), resulting in TLR ischemic tolerance. Additionally, recent studies found that postconditioning with TLR ligands after cerebral ischemia can also reduce ischemic damage through the regulation of the TLR signaling pathway, showing a significant therapeutic effect against cerebral ischemia. These studies suggest that the ischemic tolerance mediated by TLRs can serve as an important target for the prevention and treatment of cerebral ischemia. On the basis of describing the function and mechanism of TLRs in mediating cerebral ischemic damage, this review focuses on the mechanisms of cerebral ischemic tolerance induced by the preconditioning and postconditioning of TLRs and discusses the clinical application of TLRs for ischemic tolerance.

【 授权许可】

   
2015 Wang et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, et al.: Heart disease and stroke statistics-2011 update a report from the American Heart Association. Circulation 2011, 123:E18-209.
• [2]Stetler RA, Leak RK, Gan Y, Li P, Zhang F, Hu X, et al.: Preconditioning provides neuroprotection in models of CNS disease: paradigms and clinical significance. Prog Neurobiol 2014, 114:58-83.
• [3]Dirnagl U, Becker K, Meisel A: Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurol 2009, 8:398-412.
• [4]Kitagawa K, Matsumoto M, Kuwabara K, Tagaya M, Ohtsuki T, Hata R, et al.: ‘Ischemic tolerance’ phenomenon detected in various brain regions. Brain Res 1991, 561:203-11.
• [5]Lehnardt S, Lehmann S, Kaul D, Tschimmel K, Hoffmann O, Cho S, et al.: Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia. J Neuroimmunol 2007, 190:28-33.
• [6]Brea D, Blanco M, Ramos-Cabrer P, Moldes O, Arias S, Perez-Mato M, et al.: Toll-like receptors 2 and 4 in ischemic stroke: outcome and therapeutic values. J Cereb Blood Flow Metab 2011, 31:1424-31.
• [7]Caso JR, Pradillo JM, Hurtado O, Lorenzo P, Moro MA, Lizasoain I: Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 2007, 115:1599-608.
• [8]Koblansky AA, Jankovic D, Oh H, Hieny S, Sungnak W, Mathur R, et al.: Recognition of profilin by toll-like receptor 12 is critical for host resistance to toxoplasma gondii. Immunity 2013, 38:119-30.
• [9]Kawai T, Akira S: The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol 2009, 21:317-37.
• [10]Bsibsi M, Persoon-Deen C, Verwer RW, Meeuwsen S, Ravid R, Van Noort JM: Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. Glia 2006, 53:688-95.
• [11]Chattopadhyay S, Sen GC: DsRNA-activation of TLR3 and RLR signaling: gene induction-dependent and independent effects. J Interferon Cytokine Res 2014, 34:427-36.
• [12]Kawai T, Akira S: The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010, 11:373-84.
• [13]Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al.: The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001, 410:1099-103.
• [14]Uematsu S, Jang MH, Chevrier N, Guo Z, Kumagai Y, Yamamoto M, et al.: Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c + lamina propria cells. Nat Immunol 2006, 7:868-74.
• [15]Uematsu S, Fujimoto K, Jang MH, Yang BG, Jung YJ, Nishiyama M, et al.: Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat Immunol 2008, 9:769-76.
• [16]Diebold SS, Kaisho T, Hemmi H, Akira S, Sousa CRE: Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004, 303:1529-31.
• [17]Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, et al.: Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004, 303:1526-9.
• [18]Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, et al.: Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci U S A 2004, 101:5598-603.
• [19]Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A: Toll-like receptor 9-mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 2003, 198:513-20.
• [20]Krug A, Luker GD, Barchet W, Leib DA, Akira S, Colonna M: Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. Blood 2004, 103:1433-7.
• [21]Krug A, French AR, Barchet W, Fischer JAA, Dzionek A, Pingel JT, et al.: TL-139-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 2004, 21:107-19.
• [22]Yarovinsky F, Zhang DK, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, et al.: TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 2005, 308:1626-9.
• [23]Andrade WA, Souza MD, Ramos-Martinez E, Nagpal K, Dutra MS, Melo MB, et al.: Combined action of nucleic acid-sensing toll-like receptors and TLR11/TLR12 heterodimers imparts resistance to toxoplasma gondii in mice. Cell Host Microbe 2013, 13:42-53.
• [24]Kawagoe T, Sato S, Matsushita K, Kato H, Matsui K, Kumagai Y, et al.: Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat Immunol 2008, 9:684-91.
• [25]Xia ZP, Sun LJ, Chen X, Pineda G, Jiang XM, Adhikari A, et al.: Direct activation of protein kinases by unanchored polyubiquitin chains. Nature 2009, 461:114-U125.
• [26]Takeuchi O, Akira S: Pattern recognition receptors and inflammation. Cell 2010, 140:805-20.
• [27]Hacker H, Redecke V, Blagoev B, Kratchmarova I, Hsu LC, Wang GG, et al.: Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 2006, 439:204-7.
• [28]Oganesyan G, Saha SK, Guo BC, He JQ, Shahangian A, Zarnegar B, et al.: Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 2006, 439:208-11.
• [29]Shichita T, Ago T, Kamouchi M, Kitazono T, Yoshimura A, Ooboshi H: Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke. J Neurochem 2012, 123(Suppl 2):29-38.
• [30]Chamorro A, Meisel A, Planas AM, Urra X, van de Beek D, Veltkamp R: The immunology of acute stroke. Nat Rev Neurol 2012, 8:401-10.
• [31]Rubartelli A, Lotze MT: Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol 2007, 28:429-36.
• [32]Ziegler G, Harhausen D, Schepers C, Hoffmann O, Rohr C, Prinz V, et al.: TLR2 has a detrimental role in mouse transient focal cerebral ischemia. Biochem Biophys Res Commun 2007, 359:574-9.
• [33]Abe T, Shimamura M, Jackman K, Kurinami H, Anrather J, Zhou P, et al.: Key role of CD36 in toll-like receptor 2 signaling in cerebral ischemia. Stroke 2010, 41:898-904.
• [34]Ziegler G, Freyer D, Harhausen D, Khojasteh U, Nietfeld W, Trendelenburg G: Blocking TLR2 in vivo protects against accumulation of inflammatory cells and neuronal injury in experimental stroke. J Cereb Blood Flow Metab 2011, 31:757-66.
• [35]Hua F, Ma J, Ha TZ, Kelley JL, Kao RL, Schweitzer JB, et al.: Differential roles of TLR2 and TLR4 in acute focal cerebral ischemia/reperfusion injury in mice. Brain Res 2009, 1262:100-8.
• [36]Bohacek I, Cordeau P, Lalancette-Hebert M, Gorup D, Weng YC, Gajovic S, et al.: Toll-like receptor 2 deficiency leads to delayed exacerbation of ischemic injury. J Neuroinflamm 2012, 9:191. BioMed Central Full Text
• [37]Covacu R, Arvidsson L, Andersson A, Khademi M, Erlandsson-Harris H, Harris RA, et al.: TLR activation induces TNF-alpha production from adult neural stem/progenitor cells. J Immunol 2009, 182:6889-95.
• [38]Okun E, Griffioen KJ, Son TG, Lee JH, Roberts NJ, Mughal MR, et al.: TLR2 activation inhibits embryonic neural progenitor cell proliferation. J Neurochem 2010, 114:462-74.
• [39]Rolls A, Shechter R, London A, Ziv Y, Ronen A, Levy R, et al.: Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol 2007, 9:1081-8.
• [40]Hyakkoku K, Hamanaka J, Tsuruma K, Shimazawa M, Tanaka H, Uematsu S, et al.: Toll-like receptor 4 (Tlr4), but not Tlr3 or Tlr9, knock-out mice have neuroprotective effects against focal cerebral ischemia. Neuroscience 2010, 171:258-67.
• [41]Brea D, Sobrino T, Rodriguez-Yanez M, Ramos-Cabrer P, Agulla J, Rodriguez-Gonzalez R, et al.: Toll-like receptors 7 and 8 expression is associated with poor outcome and greater inflammatory response in acute ischemic stroke. Clin Immunol 2011, 139:193-8.
• [42]Alexopoulou L, Holt AC, Medzhitov R, Flavell RA: Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 2001, 413:732-8.
• [43]Cameron JS, Alexopoulou L, Sloane JA, DiBernardo AB, Ma Y, Kosaras B, et al.: Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals. J Neurosci 2007, 27:13033-41.
• [44]Lathia JD, Okun E, Tang S-C, Griffioen K, Cheng A, Mughal MR, et al.: Toll-like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation. J Neurosci 2008, 28:13978-84.
• [45]Okun E, Griffioen K, Barak B, Roberts NJ, Castro K, Pita MA, et al.: Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis. Proc Natl Acad Sci U S A 2010, 107:15625-30.
• [46]Ekdahl CT, Claasen J-H, Bonde S, Kokaia Z, Lindvall O: Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A 2003, 100:13632-7.
• [47]Cao CX, Yang QW, Lv FL, Cu J, Fu HB, Wang JZ: Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice. Biochem Biophys Res Commun 2007, 353:509-14.
• [48]Kilic U, Kilic E, Matter CM, Bassetti CL, Hermann DM: TLR-4 deficiency protects against focal cerebral ischemia and axotomy-induced neurodegeneration. Neurobiol Dis 2008, 31:33-40.
• [49]Tang SC, Arumugam TV, Xu X, Cheng A, Mughal MR, Jo DG, et al.: Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci U S A 2007, 104:13798-803.
• [50]Li XQ, Wang J, Fang B, Tan WF, Ma H: Intrathecal antagonism of microglial TLR4 reduces inflammatory damage to blood-spinal cord barrier following ischemia/reperfusion injury in rats. Mol Brain 2014, 7:28. BioMed Central Full Text
• [51]Brea D, Blanco M, Sobrino T, Ramos-Cabrer P: Castillo J [The levels of expression of toll-like receptors 2 and 4 in neutrophils are associated with the prognosis of ischaemic stroke patients]. Rev Neurol 2011, 52:12-9.
• [52]Yang QW, Li JC, Lu FL, Wen AQ, Xiang J, Zhang LL, et al.: Upregulated expression of toll-like receptor 4 in monocytes correlates with severity of acute cerebral infarction. J Cereb Blood Flow Metab 2008, 28:1588-96.
• [53]Wang CP, Li JL, Zhang LZ, Zhang XC, Yu S, Liang XM, et al.: Isoquercetin protects cortical neurons from oxygen-glucose deprivation-reperfusion induced injury via suppression of TLR4-NF-small ka, CyrillicB signal pathway. Neurochem Int 2013, 63:741-9.
• [54]Famakin BM, Mou Y, Ruetzler CA, Bembry J, Maric D, Hallenbeck JM: Disruption of downstream MyD88 or TRIF Toll-like receptor signaling does not protect against cerebral ischemia. Brain Res 2011, 1388:148-56.
• [55]Famakin B, Mou Y, Spatz M, Lawal M, Hallenbeck J: Downstream Toll-like receptor signaling mediates adaptor-specific cytokine expression following focal cerebral ischemia. J Neuroinflamm 2012, 9:174. BioMed Central Full Text
• [56]Wu D, Lee YC, Liu HC, Yuan RY, Chiou HY, Hung CH, et al.: Identification of TLR downstream pathways in stroke patients. Clin Biochem 2013, 46:1058-64.
• [57]Suga H, Sugaya M, Fujita H, Asano Y, Tada Y, Kadono T, et al.: TLR4, rather than TLR2, regulates wound healing through TGF-beta and CCL5 expression. J Dermatol Sci 2014, 73:117-24.
• [58]Tang SC, Yeh SJ, Li YI, Wang YC, Baik SH, Santro T, et al.: Evidence for a detrimental role of TLR8 in ischemic stroke. Exp Neurol 2013, 250:341-7.
• [59]Wang YC, Lin S, Yang QW: Toll-like receptors in cerebral ischemic inflammatory injury. J Neuroinflamm 2011, 8:134. BioMed Central Full Text
• [60]Vartanian KB, Stevens SL, Marsh BJ, Williams-Karnesky R, Lessov NS, Stenzel-Poore MP: LPS preconditioning redirects TLR signaling following stroke: TRIF-IRF3 plays a seminal role in mediating tolerance to ischemic injury. J Neuroinflamm 2011, 8:140. BioMed Central Full Text
• [61]Stevens SL, Stenzel-Poore MP: Toll-like receptors and tolerance to ischaemic injury in the brain. Biochem Soc Trans 2006, 34:1352-5.
• [62]Hua F, Ma J, Ha T, Kelley J, Williams DL, Kao RL, et al.: Preconditioning with a TLR2 specific ligand increases resistance to cerebral ischemia/reperfusion injury. J Neuroimmunol 2008, 199:75-82.
• [63]Marsh B, Stevens SL, Packard AEB, Gopalan B, Hunter B, Leung PY, et al.: Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke: a critical role for IRF3. J Neurosci 2009, 29:9839-49.
• [64]Leung PY, Stevens SL, Packard AEB, Lessov NS, Yang T, Conrad VK, et al.: Toll-like receptor 7 preconditioning induces robust neuroprotection against stroke by a novel type I interferon-mediated mechanism. Stroke 2012, 43:1383-9.
• [65]Packard AEB, Hedges JC, Bahjat FR, Stevens SL, Conlin MJ, Salazar AM, et al.: Poly-IC preconditioning protects against cerebral and renal ischemia-reperfusion injury. J Cereb Blood Flow Metab 2012, 32:242-7.
• [66]Stevens SL, Ciesielski TM, Marsh BJ, Yang T, Homen DS, Boule JL, et al.: Toll-like receptor 9: a new target of ischemic preconditioning in the brain. J Cereb Blood Flow Metab 2008, 28:1040-7.
• [67]Lu C, Liu L, Chen YL, Ha TZ, Kelley J, Schweitzer J, et al.: TLR2 ligand induces protection against cerebral ischemia/reperfusion injury via activation of phosphoinositide 3-kinase/Akt signaling. J Immunol 2011, 187:1458-66.
• [68]Pan LN, Zhu W, Li C, Xu XL, Guo LJ, Lu Q: Toll-like receptor 3 agonist Poly I:C protects against simulated cerebral ischemia in vitro and in vivo. Acta Pharmacol Sin 2012, 33:1246-53.
• [69]Zhang X, Ha T, Lu C, Lam F, Liu L, Schweitzer J, et al.: Poly (I:C) therapy decreases cerebral ischaemia/reperfusion injury via TLR3-mediated prevention of Fas/FADD interaction. J Cell Mol Med 2015, 19:555-65.
• [70]Gesuete R, Packard AEB, Vartanian KB, Conrad VK, Stevens SL, Bahjat FR, et al.: Poly-ICLC preconditioning protects the blood-brain barrier against ischemic injury in vitro through type I interferon signaling. J Neurochem 2012, 123:75-85.
• [71]Shi H, Gabarin N, Hickey E, Askalan R: TLR-3 receptor activation protects the very immature brain from ischemic injury. J Neuroinflamm 2013, 10:104. BioMed Central Full Text
• [72]Bhuiyan MI, Kim YJ: Mechanisms and prospects of ischemic tolerance induced by cerebral preconditioning. Int Neurourol J 2010, 14:203-12.
• [73]Pradillo JM, Fernandez-Lopez D, Garcia-Yebenes I, Sobrado M, Hurtado O, Moro MA, et al.: Toll-like receptor 4 is involved in neuroprotection afforded by ischemic preconditioning. J Neurochem 2009, 109:287-94.
• [74]Tasaki K, Ruetzler CA, Ohtsuki T, Martin D, Nawashiro H, Hallenbeck JM: Lipopolysaccharide pre-treatment induces resistance against subsequent focal cerebral ischemic damage in spontaneously hypertensive rats. Brain Res 1997, 748:267-70.
• [75]Rosenzweig HL, Lessov NS, Henshall DC, Minami M, Simon RP, Stenzel-Poore MP: Endotoxin preconditioning prevents cellular inflammatory response during ischemic neuroprotection in mice. Stroke 2004, 35:2576-81.
• [76]Hickey EJ, You XM, Kaimaktchiev V, Stenzel-Poore M, Ungerleider RM: Lipopolysaccharide preconditioning induces robust protection against brain injury resulting from deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 2007, 133:1588-96.
• [77]Lin HY, Wu CL, Huang CC: The Akt-endothelial nitric oxide synthase pathway in lipopolysaccharide preconditioning-induced hypoxic-ischemic tolerance in the neonatal Rat brain. Stroke 2010, 41:1543-51.
• [78]Rosenzweig HL, Minami M, Lessov NS, Coste SC, Stevens SL, Henshall DC, et al.: Endotoxin preconditioning protects against the cytotoxic effects of TNF alpha after stroke: a novel role for TNF alpha in LPS-ischemic tolerance. J Cereb Blood Flow Metab 2007, 27:1663-74.
• [79]Liang J, Wang J, Saad Y, Warble L, Becerra E, Kolattukudy PE: Participation of MCP-induced protein 1 in lipopolysaccharide preconditioning-induced ischemic stroke tolerance by regulating the expression of proinflammatory cytokines. J Neuroinflamm 2011, 8:182. BioMed Central Full Text
• [80]Lu C, Ha T, Wang X, Liu L, Zhang X, Kimbrough EO, et al.: The TLR9 ligand, CpG-ODN, induces protection against cerebral ischemia/reperfusion injury via activation of PI3K/Akt signaling. J Am Heart Assoc 2014., 3Article ID e000629
• [81]Stevens SL, Leung PY, Vartanian KB, Gopalan B, Yang T, Simon RP, et al.: Multiple preconditioning paradigms converge on interferon regulatory factor-dependent signaling to promote tolerance to ischemic brain injury. J Neurosci 2011, 31:8456-63.
• [82]Krieg AM: Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 2006, 5:471-84.
• [83]Medvedev AE, Lentschat A, Wahl LM, Golenbock DT, Vogel SN: Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells. J Immunol 2002, 169:5209-16.
• [84]Shi M, Deng W, Bi E, Mao K, Ji Y, Lin G, et al.: TRIM30 alpha negatively regulates TLR-mediated NF-kappa B activation by targeting TAB2 and TAB3 for degradation. Nat Immunol 2008, 9:369-77.
• [85]Sly LM, Rauh MJ, Kalesnikoff J, Song CH, Krystal G: LPS-induced upregulation of SHIP is essential for endotoxin tolerance. Immunity 2004, 21:227-39.
• [86]Kariko K, Weissman D, Welsh FA: Inhibition of toll-like receptor and cytokine signaling–a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab 2004, 24:1288-304.
• [87]Marsh BJ, Williams-Karnesky RL, Stenzel-Poore MP: Toll-like receptor signaling in endogenous neuroprotection and stroke. Neuroscience 2009, 158:1007-20.
• [88]Broad A, Kirby JA, Jones DEJ: Toll-like receptor interactions: tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-beta production. Immunology 2007, 120:103-11.
• [89]Dalpke AH, Lehner MD, Hartung T, Heeg K: Differential effects of CpG-DNA in Toll-like receptor-2/-4/-9 tolerance and cross-tolerance. Immunology 2005, 116:203-12.
• [90]Bagchi A, Herrup EA, Warren HS, Trigilio J, Shin HS, Valentine C, et al.: MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists. J Immunol 2007, 178:1164-71.
• [91]Pignataro G, Meller R, Inoue K, Ordonez AN, Ashley MD, Xiong ZG, et al.: In vivo and in vitro characterization of a novel neuroprotective strategy for stroke: ischemic postconditioning. J Cereb Blood Flow Metab 2008, 28:232-41.
• [92]Wang PF, Fang H, Chen J, Lin S, Liu Y, Xiong XY, et al.: Polyinosinic-polycytidylic acid Has therapeutic effects against cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via TLR3. J Immunol 2014, 192:4783-94.
• [93]Zhao H: Ischemic postconditioning as a novel avenue to protect against brain injury after stroke. J Cereb Blood Flow Metab 2009, 29:873-85.
• [94]Gao X, Zhang H, Takahashi T, Hsieh J, Liao J, Steinberg GK, et al.: The Akt signaling pathway contributes to postconditioning’s protection against stroke; the protection is associated with the MAPK and PKC pathways. J Neurochem 2008, 105:943-55.
• [95]Barber PA, Hach S, Tippett LJ, Ross L, Merry AF, Milsom P: Cerebral ischemic lesions on diffusion-weighted imaging are associated with neurocognitive decline after cardiac surgery. Stroke 2008, 39:1427-33.
• [96]Bahjat FR, Williams-Karnesky RL, Kohama SG, West GA, Doyle KP, Spector MD, et al.: Proof of concept: pharmacological preconditioning with a Toll-like receptor agonist protects against cerebrovascular injury in a primate model of stroke. J Cereb Blood Flow Metab 2011, 31:1229-42.
• [97]Markosian M, Hyde RM: Oligonucleotides and polyribonucleotides: a review of antiviral activity. Antivir Chem Chemother 2005, 16:91-102.
• [98]Rosenfeld MR, Chamberlain MC, Grossman SA, Peereboom DM, Lesser GJ, Batchelor TT, et al.: A multi-institution phase II study of poly-ICLC and radiotherapy with concurrent and adjuvant temozolomide in adults with newly diagnosed glioblastoma. Neuro Oncol 2010, 12:1071-7.
• [99]Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L’Huillier I, et al.: Postconditioning the human heart. Circulation 2005, 112:2143-8.