| First Author | Bracchi-Ricard V | Year | 2023 |
| Journal | FASEB J | Volume | 37 |
| Issue | 12 | Pages | e23283 |
| PubMed ID | 37983957 | Mgi Jnum | J:355491 |
| Mgi Id | MGI:7748857 | Doi | 10.1096/fj.202300769RR |
| Citation | Bracchi-Ricard V, et al. (2023) Increased activity of IRE1 improves the clinical presentation of EAE. FASEB J 37(12):e23283 |
| abstractText | Activation of the endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme-1alpha (IRE1alpha) contributes to neuronal development and is known to induce neuronal remodeling in vitro and in vivo. On the contrary, excessive IRE1 activity is often detrimental and may contribute to neurodegeneration. To determine the consequences of increased activation of IRE1alpha, we used a mouse model expressing a C148S variant of IRE1alpha with increased and sustained activation. Surprisingly, the mutation did not affect the differentiation of highly secretory antibody-producing cells but exhibited a beneficial effect in a mouse model of experimental autoimmune encephalomyelitis (EAE). Although mechanical allodynia was unaffected, significant improvement in motor function was found in IRE1C148S mice with EAE relative to wild type (WT) mice. Coincident with this improvement, there was reduced microgliosis in the spinal cord of IRE1C148S mice, with reduced expression of proinflammatory cytokine genes. This was accompanied by reduced axonal degeneration and enhanced 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) levels, suggesting improved myelin integrity. Interestingly, while the IRE1C148S mutation is expressed in all cells, the reduction in proinflammatory cytokines and in the microglial activation marker ionized calcium-binding adapter molecule (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 IRE1alpha activity can be beneficial in vivo, and that this protection is cell type and context dependent. Considering the overwhelming but conflicting evidence for the role of ER stress in neurological diseases, a better understanding of the function of ER stress sensors in physiological contexts is clearly needed. |
