Cytosolic Receptor Melanoma Differentiation–Associated Protein 5 Mediates Preconditioning-Induced Neuroprotection Against Cerebral Ischemic Injury

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.