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Accepted (AM)Open Access (License Unspecified), Open
Preprint
Increased activity of IRE1 improves the clinical presentation of EAE
bioRxiv
20 Apr 2023
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, suggesting 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.
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Details
- Title
- Increased activity of IRE1 improves the clinical presentation of EAE
- Creators
- Valerie Bracchi-Ricard - Drexel UniversityKayla Nguyen - Drexel UniversityDaniela Ricci - Children's Hospital of PhiladelphiaBrian Gaudette - University of PennsylvaniaJorge Henao-Meija - University of PennsylvaniaRoberta Brambilla - University of MiamiTetyana Martynyuk - Drexel UniversityTali Gidalevitz - Drexel UniversityDavid Allman - University of PennsylvaniaJohn R. Bethea - Drexel UniversityYair Argon - Wisconsin Disability Association
- Publication Details
- bioRxiv
- Publisher
- Cold Spring Harbor Laboratory
- Number of pages
- 35
- Resource Type
- Preprint
- Language
- English
- Academic Unit
- Biology
- Other Identifier
- 991020458321104721