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Inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurological sequelae in rheumatoid arthritis.

Journal article
Authors Karin Andersson
Caroline Wasén
Lina Juzokaite
Lovisa Leifsdottir
Malin Erlandsson
Sofia Töyrä Silfverswärd
Anna Stokowska
Marcela Pekna
Milos Pekny
Kjell Olmarker
Rolf A. Heckemann
Marie Kalm
Maria Bokarewa
Published in Proceedings of the National Academy of Sciences of the United States of America
Volume 115
Issue 51
Pages E12063-E12072
ISSN 1091-6490
Publication year 2018
Published at Institute of Clinical Sciences, Department of Radiation Physics
Institute of Neuroscience and Physiology
Institute of Medicine, Department of Rheumatology and Inflammation Research
Institute of Biomedicine
Institute of Neuroscience and Physiology, Department of Clinical Neuroscience
Pages E12063-E12072
Language en
Subject categories Rheumatology and Autoimmunity, Neuroscience


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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