Cytosolic Receptor Melanoma Differentiation-Associated Protein 5 Mediates Preconditioning-Induced Neuroprotection Against Cerebral Ischemic Injury
| Autor: | Amy E.B. Packard, Frances Rena Bahjat, Mary P. Stenzel-Poore, Sara N. Christensen, Raffaella Gesuete, Mingyue Liu, Susan L. Stevens, Andres M. Salazar |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male Interferon-Induced Helicase IFIH1 Ischemia Mice Transgenic Pharmacology Neuroprotection Article Brain Ischemia Brain ischemia DEAD-box RNA Helicases 03 medical and health sciences Mice 0302 clinical medicine Mediator Poly ICLC Medicine Animals Polylysine Receptor Ischemic Preconditioning Advanced and Specialized Nursing business.industry Melanoma medicine.disease Mice Inbred C57BL Stroke 030104 developmental biology Neuroprotective Agents Poly I-C Carboxymethylcellulose Sodium Immunology Ischemic preconditioning Neurology (clinical) Cardiology and Cardiovascular Medicine business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Stroke. 47(1) |
| ISSN: | 1524-4628 |
| Popis: | Background and Purpose— Preconditioning with poly- l -lysine and carboxymethylcellulose (ICLC) provides robust neuroprotection from cerebral ischemia in a mouse stroke model. However, the receptor that mediates neuroprotection is unknown. As a synthetic double-stranded RNA, poly-ICLC may bind endosomal Toll-like receptor 3 or one of the cytosolic retinoic acid–inducible gene-I–like receptor family members, retinoic acid–inducible gene-I, or melanoma differentiation–associated protein 5. Activation of these receptors culminates in type I interferons (IFN-α/β) induction—a response required for poly-ICLC–induced neuroprotection. In this study, we investigate the receptor required for poly-ICLC–induced neuroprotection. Methods— Toll-like receptor 3, melanoma differentiation–associated protein 5-, and IFN-promoter stimulator 1–deficient mice were treated with poly-ICLC 24 hours before middle cerebral artery occlusion. Infarct volume was measured 24 hours after stroke to identify the receptor signaling pathways involved in protection. IFN-α/β induction was measured in plasma samples collected 6 hours after poly-ICLC treatment. IFN-β–deficient mice were used to test the requirement of IFN-β for poly-ICLC–induced neuroprotection. Mice were treated with recombinant IFN-α-A to test the role of IFN-α as a potential mediator of neuroprotection. Results— Poly-ICLC induction of both neuroprotection and systemic IFN-α/β requires the cytosolic receptor melanoma differentiation–associated protein 5 and the adapter molecule IFN-promoter stimulator 1, whereas it is independent of Toll-like receptor 3. IFN-β is not required for poly-ICLC–induced neuroprotection. IFN-α treatment protects against stroke. Conclusions— Poly-ICLC preconditioning is mediated by melanoma differentiation–associated protein 5 and its adaptor molecule IFN-promoter stimulator 1. This is the first evidence that a cytosolic receptor can mediate neuroprotection, providing a new target for the development of therapeutic agents to protect the brain from ischemic injury. |
| Databáze: | OpenAIRE |
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