title: Astrogliosis involves activation of retinoic acid-inducible gene-like signaling in the innate immune response after spinal cord injury.
abstract: Spinal cord injury (SCI) induces a glial response in which astrocytes become activated and produce inflammatory mediators. The molecular basis for regulation of glial-innate immune responses remains poorly understood. Here, we examined the activation of retinoic acid-inducible gene (RIG)-like receptors (RLRs) and their involvement in regulating inflammation after SCI. We show that astrocytes express two intracellular RLRs: RIG-I and melanoma differentiation-associated gene 5. SCI and stretch injury of cultured astrocytes stimulated RLR signaling as determined by phosphorylation of interferon regulatory factor 3 (IRF3) leading to production of type I interferons (IFNs). RLR signaling stimulation with synthetic ribonucleic acid resulted in RLR activation, phosphorylation of IRF3, and increased expression of glial fibrillary acidic protein (GFAP) and vimentin, two hallmarks of reactive astrocytes. Moreover, mitochondrial E3 ubiquitin protein ligase 1, an RLR inhibitor, decreased production of GFAP and vimentin after RIG-I signaling stimulation. Our findings identify a role for RLR signaling and type I IFN in regulating astrocyte innate immune responses after SCI.
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, Florida, USA. JdeRivero@med.miami.edu
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: de Rivero Vaccari
authors.forename: Julia
authors.initials: J
authors.lastname: Minkiewicz
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: De Rivero Vaccari
authors.forename: Ramon
authors.initials: R
authors.lastname: German
authors.forename: Alex E
authors.initials: AE
authors.lastname: Marcillo
authors.forename: W Dalton
authors.initials: WD
authors.lastname: Dietrich
authors.forename: Robert W
authors.initials: RW
authors.lastname: Keane
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C / Q000494:pharmacology; D020365:RNA Helicases / Q000378:metabolism* / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000276:immunology* / Q000378:metabolism*; D013314:Stress, Mechanical; D013997:Time Factors; D014746:Vimentin / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D012330:RNA, Double-Stranded; D014746:Vimentin; C556407:RIG-I protein, rat; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D020365:RNA Helicases; D011070:Poly I-C