SignificanceAberrant insulin-like growth factor 1 receptor (IGF1R)/insulin receptor signaling in brain has recently been linked to neurodegeneration in diabetes mellitus and in Alzheimer’s disease. In this study, we demonstrate that functional disability and pain in patients with rheumatoid arthritis (RA) and in experimental RA are associated with hippocampal inflammation and inhibition of IGF1R/insulin receptor substrate 1 (IRS1) signal, reproducing an IGF1/insulin-resistant state. This restricts formation of new neurons in the hippocampus, reduces hippocampal volume, and predisposes RA patients to develop neurological symptoms. Improving IRS1 function through down-regulation of IGF1R disinhibits neurogenesis and can potentially ameliorate neurological symptoms. This opens perspectives for drugs that revert IGF1/insulin resistance as an essential complement to the antirheumatic and antiinflammatory arsenal.

IntroductionIn addition to inflammation of the joints, rheumatoid arthritis (RA) has a neurological part consisting of pain, fatigue, depression and cognitive deterioration. These symptoms are critical for the patients’ ability to cope with daily life, but are not alleviated completely with modern antirheumatic drugs. Sufficient IGF1R signalling is important for neurogenesis in the hippocampus. Its misbalance correlates with depression and anxiety.ObjectivesThe aim of this study was to evaluate the pathological changes in the brain during experimental RA and investigate their connexion to IGF1R.MethodsCharacteristics of pain, depression and anxiety were collected among 214 RA patients and analysed in relation to IGF1R expression in WBC. Experimental RA was induced by immunisation with collagen II. Inhibition of IGF1R was achieved by injection of shRNA-producing lentiviral construct. The behavioural pattern of each mouse was recorded by filming. The hippocampus was analysed morphometrically, and gene and protein expression were analysed by qPCR and immunohistochemistry, respectively.ResultsThe RA patients’ perception of depression and anxiety was associated with high IGF1R expression in WBC. This group of patients was also less physically active. In experimental RA, an enrichment of IBA1 +microglia and high expression of CD68 and IL-1b was found in the hippocampus. This was followed by an increased density of IGF1R+cells in cornu ammoni, and a decreased neurogenesis by limited expression DCX in the subgranular layer of the dentate gyrus. This results in a significant reduction of the hippocampus area. These changes in the brain were associated with immobility in RA mice. Treatment with shRNA targeting IGF1R improved arthritis, but led to increased immobility.ConclusionsRA induces remote inflammation in the hippocampus reducing neurogenesis and physical activity. The neurological symptoms in patients and in experimental RA are connected to IGF1R expression and signalling, and further expands our knowledge of neurological processes in RA.Disclosure of interestNone declared