title: Cytosolic Receptor Melanoma Differentiation-Associated Protein 5 Mediates Preconditioning-Induced Neuroprotection Against Cerebral Ischemic Injury.
abstract: OBJECTIVE
  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.affiliation: From the Department of Molecular Microbiology and Immunology, Oregon Health and Sciences University, Portland, OR (R.G., S.N.C., F.R.B., A.E.B.P., S.L.S., M.L., M.P.S.-P.); and Oncovir, Washington, DC (A.M.S.).
authors.forename: Raffaella
authors.initials: R
authors.lastname: Gesuete
authors.affiliation: From the Department of Molecular Microbiology and Immunology, Oregon Health and Sciences University, Portland, OR (R.G., S.N.C., F.R.B., A.E.B.P., S.L.S., M.L., M.P.S.-P.); and Oncovir, Washington, DC (A.M.S.).
authors.forename: Sara N
authors.initials: SN
authors.lastname: Christensen
authors.affiliation: From the Department of Molecular Microbiology and Immunology, Oregon Health and Sciences University, Portland, OR (R.G., S.N.C., F.R.B., A.E.B.P., S.L.S., M.L., M.P.S.-P.); and Oncovir, Washington, DC (A.M.S.).
authors.forename: Frances R
authors.initials: FR
authors.lastname: Bahjat
authors.affiliation: From the Department of Molecular Microbiology and Immunology, Oregon Health and Sciences University, Portland, OR (R.G., S.N.C., F.R.B., A.E.B.P., S.L.S., M.L., M.P.S.-P.); and Oncovir, Washington, DC (A.M.S.).
authors.forename: Amy E B
authors.initials: AE
authors.lastname: Packard
authors.affiliation: From the Department of Molecular Microbiology and Immunology, Oregon Health and Sciences University, Portland, OR (R.G., S.N.C., F.R.B., A.E.B.P., S.L.S., M.L., M.P.S.-P.); and Oncovir, Washington, DC (A.M.S.).
authors.forename: Susan L
authors.initials: SL
authors.lastname: Stevens
authors.affiliation: From the Department of Molecular Microbiology and Immunology, Oregon Health and Sciences University, Portland, OR (R.G., S.N.C., F.R.B., A.E.B.P., S.L.S., M.L., M.P.S.-P.); and Oncovir, Washington, DC (A.M.S.).
authors.forename: Mingyue
authors.initials: M
authors.lastname: Liu
authors.affiliation: From the Department of Molecular Microbiology and Immunology, Oregon Health and Sciences University, Portland, OR (R.G., S.N.C., F.R.B., A.E.B.P., S.L.S., M.L., M.P.S.-P.); and Oncovir, Washington, DC (A.M.S.).
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.affiliation: From the Department of Molecular Microbiology and Immunology, Oregon Health and Sciences University, Portland, OR (R.G., S.N.C., F.R.B., A.E.B.P., S.L.S., M.L., M.P.S.-P.); and Oncovir, Washington, DC (A.M.S.). poorem@ohsu.edu.
authors.forename: Mary P
authors.initials: MP
authors.lastname: Stenzel-Poore
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000517:prevention & control*; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D000072640:Interferon-Induced Helicase, IFIH1; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use; D011070:Poly I-C / Q000378:metabolism / Q000627:therapeutic use; D011107:Polylysine / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D020521:Stroke / Q000378:metabolism* / Q000517:prevention & control*
chemical_list: D018696:Neuroprotective Agents; D011107:Polylysine; C019531:poly ICLC; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C
keywords: interferons; ischemia; ischemia-reperfusion injury; poly ICLC; toll-like receptors