Poly-ICLC preconditioning protects the blood-brain barrier against ischemic injury in vitro through type I interferon signaling.
Preconditioning with a low dose of harmful stimulus prior to injury induces tolerance to a subsequent ischemic challenge resulting in neuroprotection against stroke. Experimental models of preconditioning primarily focus on neurons as the cellular target of cerebral protection, while less attention has been paid to the cerebrovascular compartment, whose role in the pathogenesis of ischemic brain injury is crucial. We have shown that preconditioning with polyinosinic polycytidylic acid (poly-ICLC) protects against cerebral ischemic damage. To delineate the mechanism of poly-ICLC protection, we investigated whether poly-ICLC preconditioning preserves the function of the blood-brain barrier (BBB) in response to ischemic injury. Using an in vitro BBB model, we found that poly-ICLC treatment prior to exposure to oxygen-glucose deprivation maintained the paracellular and transcellular transport across the endothelium and attenuated the drop in transendothelial electric resistance. We found that poly-ICLC treatment induced interferon (IFN) β mRNA expression in astrocytes and microglia and that type I IFN signaling in brain microvascular endothelial cells was required for protection. Importantly, this implicates a potential mechanism underlying neuroprotection in our in vivo experimental stroke model, where type I IFN signaling is required for poly-ICLC-induced neuroprotection against ischemic injury. In conclusion, we are the first to show that preconditioning with poly-ICLC attenuates ischemia-induced BBB dysfunction. This mechanism is likely an important feature of poly-ICLC-mediated neuroprotection and highlights the therapeutic potential of targeting BBB signaling pathways to protect the brain against stroke.
Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon 97239, USA.
Raffaella
R
Gesuete
Amy E B
AE
Packard
Keri B
KB
Vartanian
Valerie K
VK
Conrad
Susan L
SL
Stevens
Frances R
FR
Bahjat
Tao
T
Yang
Mary P
MP
Stenzel-Poore
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D002266:Carboxymethylcellulose Sodium / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000235:genetics / Q000517:prevention & control*; D050856:Interferon Regulatory Factor-1 / Q000172:deficiency / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D019194:Ischemic Preconditioning / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011070:Poly I-C / Q000008:administration & dosage* / Q000494:pharmacology; D011107:Polylysine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019108:Tight Junctions / Q000187:drug effects / Q000473:pathology; D013997:Time Factors
D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D011107:Polylysine; D016899:Interferon-beta; C019531:poly ICLC; D005947:Glucose; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C