title: Injury-induced type I IFN signaling regulates inflammatory responses in the central nervous system.
abstract: Innate glial response is critical for the induction of inflammatory mediators and recruitment of leukocytes to sites of the injury in the CNS. We have examined the involvement of type I IFN signaling in the mouse hippocampus following sterile injury (transection of entorhinal afferents). Type I IFNs signal through a receptor (IFNAR), which involves activation of IFN regulatory factor (IRF)9, leading to the induction of IFN-stimulated genes including IRF7, that in turn enhances the induction of type I IFN. Axonal transection induced upregulation of IRF7 and IRF9 in hippocampus. Induction of IRF7 and IRF9 mRNAs was IFNAR dependent. Double-labeling immunofluorescence showed that IRF7 selectively was induced in Mac-1/CD11b(+) macrophages/microglia in hippocampus after axonal transection. IRF7 mRNA was also detected in microglia sorted by flow cytometry. Lack of type I IFN signaling resulted in increased leukocyte infiltration into the lesion-reactive hippocampus. Axonal lesion-induced CXCL10 gene expression was abrogated, whereas matrix metalloproteinase 9 mRNA was elevated in IFNAR-deficient mice. Our findings point to a role for type I IFN signaling in regulation of CNS response to sterile injury.
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Reza
authors.initials: R
authors.lastname: Khorooshi
authors.forename: Trevor
authors.initials: T
authors.lastname: Owens
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000276:immunology; D039481:CD11b Antigen / Q000032:analysis; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006624:Hippocampus / Q000293:injuries / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D039481:CD11b Antigen; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D018836:Inflammation Mediators; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; C494235:Irf7 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D053633:Receptor, Interferon alpha-beta; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse