Cytosolic receptor melanoma differentiation-associated protein 5 mediates preconditioning-induced neuroprotection against cerebral ischemic injury

Raffaella Gesuete, Sara N. Christensen, Frances Bahjat, Amy E B Packard, Susan L. Stevens, Mingyue Liu, Andres M. Salazar, Mary Stenzel-Poore

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)262-266
Number of pages5
JournalStroke
Volume47
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

Wounds and Injuries
Toll-Like Receptor 3
Stroke
Tretinoin
Interferons
IFIH1 Interferon-Induced Helicase
poly ICLC
Neuroprotection
Interferon Type I
Carboxymethylcellulose Sodium
Double-Stranded RNA
Middle Cerebral Artery Infarction
Brain Ischemia
Brain Injuries
Genes
Lysine
Therapeutics

Keywords

  • interferons
  • ischemia
  • ischemia-reperfusion injury
  • poly ICLC
  • toll-like receptors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing

Cite this

Cytosolic receptor melanoma differentiation-associated protein 5 mediates preconditioning-induced neuroprotection against cerebral ischemic injury. / Gesuete, Raffaella; Christensen, Sara N.; Bahjat, Frances; Packard, Amy E B; Stevens, Susan L.; Liu, Mingyue; Salazar, Andres M.; Stenzel-Poore, Mary.

In: Stroke, Vol. 47, No. 1, 01.01.2016, p. 262-266.

Research output: Contribution to journalArticle

Gesuete, Raffaella ; Christensen, Sara N. ; Bahjat, Frances ; Packard, Amy E B ; Stevens, Susan L. ; Liu, Mingyue ; Salazar, Andres M. ; Stenzel-Poore, Mary. / Cytosolic receptor melanoma differentiation-associated protein 5 mediates preconditioning-induced neuroprotection against cerebral ischemic injury. In: Stroke. 2016 ; Vol. 47, No. 1. pp. 262-266.
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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.",
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AU - Bahjat, Frances

AU - Packard, Amy E B

AU - Stevens, Susan L.

AU - Liu, Mingyue

AU - Salazar, Andres M.

AU - Stenzel-Poore, Mary

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N2 - 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.

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