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

Abstract

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.

• Authors: Raffaella Gesuete, Sara N Christensen, Frances R Bahjat, Amy E B Packard, Susan L Stevens, Mingyue Liu, Andres M Salazar, Mary P Stenzel-Poore
• Journal: Stroke (Stroke) Vol. 47 Issue 1 Pg. 262-6 (Jan 2016) ISSN: 1524-4628 [Electronic] United States
• PMID: 26564103 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Neuroprotective Agents
• Polylysine
• poly ICLC
• Ifih1 protein, mouse
• DEAD-box RNA Helicases
• Interferon-Induced Helicase, IFIH1
• Carboxymethylcellulose Sodium
• Poly I-C

Topics

• Animals
• Brain Ischemia (metabolism, prevention & control)
• Carboxymethylcellulose Sodium (analogs & derivatives, metabolism, therapeutic use)
• DEAD-box RNA Helicases (metabolism)
• Interferon-Induced Helicase, IFIH1
• Ischemic Preconditioning (methods)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neuroprotective Agents (metabolism, therapeutic use)
• Poly I-C (metabolism, therapeutic use)
• Polylysine (analogs & derivatives, metabolism, therapeutic use)
• Stroke (metabolism, prevention & control)