Hippocampal neuroinflammation and altered peripheral neurobiological protein profile in experimental arthritis and systemic juvenile idiopathic arthritis

BACKGROUND: Children with juvenile idiopathic arthritis (JIA) are reported to exhibit increased rates of symptoms affecting emotional regulation and behaviour. However, underlying biological mechanisms remain unclear. Inflammation in the central nervous system (CNS) can be triggered by peripheral immune effects and may contribute to these observations. In this study, we aimed to investigate whether neurobiological alterations are present in systemic JIA (sJIA), whether CNS inflammation occurs during arthritis, and the potential underlying mechanisms. METHODS: Plasma samples from patients with active sJIA (n = 16) and sex- and age-matched healthy controls (HCs, n = 16), together with paired samples from the same patients with sJIA during inactive disease (n = 12), were analysed using Olink proteomics to determine peripheral neurobiological and inflammation protein profiles. Clinical data was retrieved from the Swedish Paediatric Rheumatology Register and medical charts. CNS neuroinflammatory responses and underlying mechanisms were further investigated using in vivo and in vitro experiments. FINDINGS: Patients with active sJIA exhibited altered plasma neurobiological protein profiles compared with HCs. These alterations correlated with higher scores of pain and life impact in patients, suggesting that the altered profiles may reflect neurofunctional changes. Notably, the neurobiological protein profiles remained altered even during inactive phases of the disease. In chronic arthritic mice, microglial activation and impaired neurogenesis were observed in the hippocampus, with no significant cortical changes. RNA-seq analysis implicated mitochondrial dysfunction and oxidative stress in mediating neuroinflammation during chronic arthritis in mice. Haem oxygenase 2 (HMOX2) was identified as a peripheral biomarker indicating microglial activation in the hippocampus (Spearman r = -0.886, P = 0.019). Combined neurobiological and inflammation profiling in patients with sJIA implicated interleukin-6 (IL-6) and interleukin-18 (IL-18) as potential drivers of hippocampal microglial activation during arthritis. INTERPRETATION: Our findings highlight the effects of sJIA and experimental arthritis on the nervous system and provide insights for clinical monitoring and the development of targeted therapeutic strategies. FUNDING: This study was funded by grants from the Swedish Research Council and The Swedish Rheumatism Association.