Toll-Like Receptor 7 Preconditioning Induces Robust Neuroprotection Against Stroke by a Novel Type I Interferon-Mediated Mechanism

Systemic administration of Toll-like receptor (TLR) 4 and TLR9 agonists before cerebral ischemia have been shown to reduce ischemic injury by reprogramming the response of the brain to stroke. Our goal was to explore the mechanism of TLR-induced neuroprotection by determining whether a TLR7 agonist...

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Bibliographic Details
Published in:Stroke (1970) 2012-05, Vol.43 (5), p.1383-1389
Main Authors: LEUNG, Philberta Y, STEVENS, Susan L, PACKARD, Amy E. B, LESSOV, Nikola S, TAO YANG, CONRAD, Valerie K, DEN DUNGEN, Noortje N. A. M. Van, SIMON, Roger P, STENZEL-POORE, Mary P
Format: Article
Language:English
Subjects:
Aminoquinolines - therapeutic use
Animals
Biological and medical sciences
Brain - blood supply
Brain Infarction - pathology
Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy
Imidazoles - therapeutic use
Interferon Regulatory Factor-7 - deficiency
Interferon Regulatory Factor-7 - genetics
Interferon Regulatory Factor-7 - physiology
Ischemic Preconditioning - methods
Male
Medical sciences
Membrane Glycoproteins - agonists
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Animal
Nervous system (semeiology, syndromes)
Neurology
Neuroprotective Agents - therapeutic use
Receptor, Interferon alpha-beta - deficiency
Receptor, Interferon alpha-beta - genetics
Receptor, Interferon alpha-beta - physiology
Signal Transduction - physiology
Stroke - physiopathology
Stroke - prevention & control
Toll-Like Receptor 7 - agonists
Tumor Necrosis Factor-alpha - deficiency
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - physiology
Vascular diseases and vascular malformations of the nervous system
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Summary:Systemic administration of Toll-like receptor (TLR) 4 and TLR9 agonists before cerebral ischemia have been shown to reduce ischemic injury by reprogramming the response of the brain to stroke. Our goal was to explore the mechanism of TLR-induced neuroprotection by determining whether a TLR7 agonist also protects against stroke injury. C57Bl/6, TNF(-/-), interferon (IFN) regulatory factor 7(-/-), or type I IFN receptor (IFNAR)(-/-) mice were subcutaneously administered the TLR7 agonist Gardiquimod (GDQ) 72 hours before middle cerebral artery occlusion. Infarct volume and functional outcome were determined after reperfusion. Plasma cytokine responses and induction of mRNA for IFN-related genes in the brain were measured. IFNAR(-/-) mice also were treated with the TLR4 agonist (lipopolysaccharide) or the TLR9 agonist before middle cerebral artery occlusion and infarct volumes measured. The results show that GDQ reduces infarct volume as well as functional deficits in mice. GDQ pretreatment provided robust neuroprotection in TNF(-/-) mice, indicating that TNF was not essential. GDQ induced a significant increase in plasma IFNα levels and both IRF7(-/-) and IFNAR(-/-) mice failed to be protected, implicating a role for IFN signaling in TLR7-mediated protection. Our studies provide the first evidence that TLR7 preconditioning can mediate neuroprotection against ischemic injury. Moreover, we show that the mechanism of protection is unique from other TLR preconditioning ligands in that it is independent of TNF and dependent on IFNAR.
ISSN:0039-2499
1524-4628
DOI:10.1161/strokeaha.111.641522