Background/Purpose: Depression and cognitive impairment are frequently reported in rheumatoid arthritis (RA). We have recently presented that reduced hippocampus volume may be linked to functional disability and enhanced pain response in patients with RA (Andersson and Wasén et al. 2018). Reduced hippocampus volume and reduced neurogenesis (in hippocampus) was suggested related to insulin-like growth-factor 1 (IGF1) signaling in both RA patients and experimental models. Here, we aim to investigate the relation between growth factors of importance for neuronal growth and inflammation in RA and experimental arthritis.

Methods: Serum of 254 RA patients was analyzed for inflammatory markers IL-1b and IL-6 in addition to growth factors IGF1, brain-derived neurotrophic factor (BNDF) and vascular endothelial growth-factor (VEGF) and compared to the patients’ disease activity (DAS28). Mice with collagen-induced arthritis were treated with short hairpin (sh)RNA targeting expression of IGF1 receptor (IGF1R). IBA1⁺ (microglia), DCX⁺ (developing neurons) and serin256-phosphorylated FoxO1⁺ (target of IGF1 signaling) cells in the hippocampal structures dentate gyrus (DG) and cornu ammonis (CA1-3) were identified by immunohistochemistry.

Results: Serum levels of IGF1, BNDF and VEGF all had weak but significant correlations to IL-1b (r= 0.12, 0.20 and 0.19, p= 0.049, 0.0013 and 0.0032, respectively). IGF1 was inversely correlated to IL-6 levels (r= -0.15, p= 0.020) and BNDF was negatively associated with disease activity (r= -0.14, p= 0.038). High serum IGF1 was associated with less expression of IGF1R in human peripheral blood monocytes (r= 0.25 p= 0.023). In IGF1R inhibited mice, the density of IBA1⁺ microglial cells was decreased in DG and CA regions of the hippocampus, indicating reduced local inflammation. The density of pFoxO1⁺ cells was increased in DG (p=0.0046) and CA3 (p=0.0030) when IGF1R was inhibited. The density of pFoxO1⁺ cells in DG and CA3 was positively correlated with serum IGF1 (r= 0.64 and 0.51, p= 0.0006 and 0.0080). However, the density of pFoxO1⁺ cells in DG and CA3 was negatively correlated with the number of DCX⁺ developing neurons (r= -0.46 and -0.65, p= 0.078 and 0.014).

Conclusion: We conclude that systemic inflammation measured as higher disease activity and IL-6 levels were associated with low BNDF, while serum IL-1b may stimulate release of growth factors IGF1, BNDF and VEGF into serum. Inhibition of IGF1R resulted in increased serum levels of IGF1, increased FoxO1 phosphorylation in the hippocampus, but this appeared to be insufficient to rescue neurogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inflammation-and-neuronal-growth-factors-in-rheumatoid-arthritis/