Hippocampal Neuroinflammation and Altered Peripheral Neurobiological Protein Profile in Experimental Arthritis and Systemic Juvenile Idiopathic Arthritis

Abstract

BackgroundChildren with juvenile idiopathic arthritis (JIA) are reported to exhibit increased rates of symptoms affecting emotional regulation and behavior. However, underlying biological mechanisms remain unclear. Neuroinflammation 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 if neurobiological alterations are present in systemic JIA (sJIA), and if CNS neuroinflammation occurs during arthritis, and to explore the potential mechanisms involved. MethodsPlasma 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 sJIA patients during inactive disease (n = 12), were analyzed using Olink proteomics to determine the peripheral neurobiological and inflammation protein profiles. Clinical data was retrieved from the Swedish Pediatric Rheumatology Register and medical charts. CNS Neuroinflammatory responses and underlying mechanisms were further explored through in vivo and in vitro experiments. FindingsActive sJIA patients exhibited altered 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 in the patients. Notably, the neurobiological protein profile remained altered even during the inactive phase of the disease. In chronic arthritic mice, microglial activation and impaired neurogenesis were observed in hippocampus, with no significant cortical changes. RNA-seq analysis implicated mitochondrial dysfunction and oxidative stress in mediating neuroinflammation during chronic arthritis in mice. Heme oxygenase 2 (HMOX2) was identified as a peripheral biomarker indicating hippocampal microglia activation. Combined neurobiological and inflammation profiling in sJIA patients implicated Interleukin-6 (IL-6) and Interleukin-18 (IL-18) as key drivers of hippocampal microglia activation during arthritis. InterpretationChronic arthritis is associated with neuroinflammation and altered neurobiological protein profiles in sJIA. HMOX2 emerges as a promising plasma biomarker of CNS changes. IL-6 and especially IL-18 are indicated as key drivers of neuroinflammatory processes. These findings offer insights for clinical monitoring and targeted therapies. FundingThis study was funded by grants from the Swedish Research Council and The Swedish Rheumatism Association. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSChildren with juvenile idiopathic arthritis (JIA) have increased rates of emotional and behavioral disturbances compared with healthy peers. Systemic inflammation and chronic arthritis are suspected to affect the central nervous system, but biological mechanisms in systemic JIA (sJIA) are poorly understood. Added value of this studyIn this study, we demonstrate patients with sJIA have a distinct plasma neurobiological protein profile compared with healthy controls, which correlate with higher pain and life impact scores. In chronic arthritic mice, hippocampal microglial activation, impaired neurogenesis, and mitochondrial dysfunction with oxidative stress are presented. By combining patient and mouse data, we identify heme oxygenase 2 (HMOX2) as a candidate plasma biomarker of hippocampal neuroinflammation and implicate IL-6, and especially IL-18, as key mediators linking chronic arthritis to neurobiological changes. Implications of all the available evidenceThis study provides molecular evidence that neurobiological alterations in sJIA patients and supports incorporating neurobiological and neuropsychiatric monitoring into the clinical follow-up of children with sJIA. We highlight the mechanistic targets and measurable biomarkers (e.g. HMOX2) for future studies and trials aiming to modulate neuroinflammation in chronic arthritis. This study may inform the development of personalized treatment strategies, including IL-18-directed therapies, for patients at risk of neurological or psychosocial complications.