Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 51, Pages E12063-E12072Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1810553115
Keywords
arthritis; IGF1 receptor; hippocampus; pain; MRI
Categories
Funding
- Swedish Research Council [521-2011-2414, 521-2014-2637]
- Medical Society of Gothenburg
- Swedish Rheumatology Association [R-566961, R-477321]
- King Gustaf V's 80-Year Foundation [FAI-2014-0016]
- Torsten Soderberg's Foundation
- Rune and Ulla Amlovs Trust
- Lundberg's Foundation
- regional agreement on medical training and clinical research [ALFGBG-671631]
- UK Medical Research Council [MR/L01632X/1]
- MRC [MR/L01632X/1] Funding Source: UKRI
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Rheumatoid arthritis (RA) is an inflammatory joint disease with a neurological component including depression, cognitive deficits, and pain, which substantially affect patients' quality of daily life. Insulin-like growth factor 1 receptor (IGF1R) signaling is one of the factors in RA pathogenesis as well as a known regulator of adult neurogenesis. The purpose of this study was to investigate the association between IGF1R signaling and the neurological symptoms in RA. In experimental RA, we demonstrated that arthritis induced enrichment of IBA1(+) microglia in the hippocampus. This coincided with inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) and up-regulation of IGF1R in the pyramidal cell layer of the cornus ammoni and in the dentate gyrus, reproducing the molecular features of the IGF1/insulin resistance. The aberrant IGF1R signaling was associated with reduced hippocampal neurogenesis, smaller hippocampus, and increased immobility of RA mice. Inhibition of IGF1R in experimental RA led to a reduction of IRS1 inhibition and partial improvement of neurogenesis. Evaluation of physical functioning and brain imaging in RA patients revealed that enhanced functional disability is linked with smaller hippocampus volume and aberrant IGF1R/IRS1 signaling. These results point to abnormal IGF1R signaling in the brain as a mediator of neurological sequelae in RA and provide support for the potentially reversible nature of hippocampal changes.
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