Increased activity of IRE1 improves the clinical presentation of EAE
Increased activity of IRE1 improves the clinical presentation of EAE
Abstract Activation of the ER stress sensor IRE1α contributes to neuronal development and is known to induce neuronal remodeling in vitro and in vivo. On the other hand, excessive IRE1 activity is often detrimental and may contribute to neurodegeneration. To determine the consequences of increased activation of IRE1α, we used a mouse model expressing a C148S variant of IRE1α with increased and sustained activation. Surprisingly, the mutation did not affect the differentiation of highly secretory antibody-producing cells, but exhibited a strong protective effect in a mouse model of experimental autoimmune encephalomyelitis (EAE). Significant improvement in motor function was found in IRE1C148S mice with EAE relative to WT mice. Coincident with this improvement, there was reduced microgliosis in the spinal cord of IRE1C148S mice, with reduced expression of pro-inflammatory cytokine genes. This was accompanied by reduced axonal degeneration and enhanced CNPase levels, suggestiing improved myelin integrity. Interestingly, while the IRE1C148S mutation is expressed in all cells, the reduction in proinflammatory cytokines and in the activation of microglial activation marker IBA1, along with preservation of phagocytic gene expression, all point to microglia as the cell type contributing to the clinical improvement in IRE1C148S animals. Our data suggest that sustained increase in IRE1α activity can be protective in vivo, and that this protection is cell type and context dependent. Considering the overwhelming but conflicting evidence for the role of the ER stress in neurological diseases, a better understanding of the function of ER stress sensors in physiological contexts is clearly needed.
Bracchi-Ricard Valerie、Brambilla Roberta、Nguyen Kayla、Ricci Daniela、Henao-Meija Jorge、Gaudette Brian、Argon Yair、Allman David、Bethea John R.、Gidalevitz Tali、Martynyuk Tetyana
Department of Biology, Drexel UniversityThe Miami Project to Cure Paralysis, University of Miami Miller School of Medicine||Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark||BRIDGE - Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern DenmarkDepartment of Biology, Drexel UniversityDepartment of Pathology and Lab Medicine, The Children?ˉs Hospital of Philadelphia and the University of PennsylvaniaDepartment of Pathology and Lab Medicine, The Children?ˉs Hospital of Philadelphia and the University of PennsylvaniaDepartment of Pathology and Lab Medicine, the University of PennsylvaniaDepartment of Pathology and Lab Medicine, The Children?ˉs Hospital of Philadelphia and the University of PennsylvaniaDepartment of Pathology and Lab Medicine, the University of PennsylvaniaDepartment of Biology, Drexel UniversityDepartment of Biology, Drexel UniversityDepartment of Biology, Drexel University
神经病学、精神病学基础医学生物科学研究方法、生物科学研究技术
Augmented IRE1α activityUnfolded protein responseNeuroinflammationAlternatively activated microgliaExperimental Autoimmune Encephalomyelitis
Bracchi-Ricard Valerie,Brambilla Roberta,Nguyen Kayla,Ricci Daniela,Henao-Meija Jorge,Gaudette Brian,Argon Yair,Allman David,Bethea John R.,Gidalevitz Tali,Martynyuk Tetyana.Increased activity of IRE1 improves the clinical presentation of EAE[EB/OL].(2025-03-28)[2025-06-06].https://www.biorxiv.org/content/10.1101/2023.04.19.537391.点此复制
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