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

Stroke. 2016 Jan;47(1):262-6. doi: 10.1161/STROKEAHA.115.010329. Epub 2015 Nov 12.


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.

Keywords: interferons; ischemia; ischemia-reperfusion injury; poly ICLC; toll-like receptors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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


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