title: A new role for downstream Toll-like receptor signaling in mediating immediate early gene expression during focal cerebral ischemia.
abstract: To better understand the role of downstream Toll-like receptor (TLR) signaling during acute cerebral ischemia, we performed cDNA microarrays, on brain RNA, and cytokine arrays, on serum, from wild type (WT), MyD88-/- and TRIF-mutant mice, at baseline and following permanent middle cerebral artery occlusion (pMCAO). The acute stress response pathway was among the top pathways identified by Ingenuity Pathway Analysis of microarray data. We used real-time polymerase chain reaction to confirm the expression of four immediate early genes; EGR1, EGR2, ARC, Nurr77, in this pathway, and insulin degrading enzyme (IDE). Compared to WT, baseline immediate early gene expression was increased up to10-fold in MyD88-/- and TRIF-mutant mice. However, following pMCAO, immediate early gene expression remained unchanged, from this elevated baseline in these mice, but increased up to 12-fold in WT. Furthermore, expression of IDE, which also degrades β-amyloid, decreased significantly only in TRIF-mutant mice. Finally, sE-Selectin, sICAM, sVCAM-1, and MMP-9 levels were significantly decreased only in MyD88-/- compared with WT mice. We thus report a new role for downstream TLR signaling in immediate early gene expression during acute cerebral ischemia. We also show that the TRIF pathway regulates IDE expression; a major enzyme that clears β-amyloid from the brain.
authors.affiliation: National Institute of Neurological Disorders and Stroke, Stroke Branch, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Bolanle M
authors.initials: BM
authors.lastname: Famakin
authors.affiliation: National Institute of Neurological Disorders and Stroke, Stroke Branch, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Yongshan
authors.initials: Y
authors.lastname: Mou
authors.affiliation: National Institute of Neurological Disorders & Stroke, Section on Bioinformatics, Information Technology & Bioinformatics Program, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kory
authors.initials: K
authors.lastname: Johnson
authors.affiliation: National Institute of Neurological Disorders and Stroke, Stroke Branch, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Spatz
authors.affiliation: National Institute of Neurological Disorders and Stroke, Stroke Branch, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: John
authors.initials: J
authors.lastname: Hallenbeck
mesh_terms: D000208:Acute Disease; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D007339:Insulysin / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D051766:Early Growth Response Protein 1; D051767:Early Growth Response Protein 2; D007339:Insulysin; D020780:Matrix Metalloproteinase 9; D053594:Myeloid Differentiation Factor 88; D009419:Nerve Tissue Proteins; D051193:Toll-Like Receptors; C486109:Egr1 protein, mouse; C497327:Egr2 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C092069:activity regulated cytoskeletal-associated protein; C501830:Mmp9 protein, mouse