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

Overview

Authors: Xingzhao Wen¹, Heshuang Qu¹, Malgorzata Benedyk-Machaczka², Daphne Chen¹, Erik Sundberg^3,4, Erik Melén⁵, Maria Altman^3,4, Cecilia Aulin¹, Helena Erlandsson Harris^1,6

ORCID iDs: Heshuang Qu, Malgorzata Benedyk-Machaczka

Division of Rheumatology, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
Unit of Paediatric Rheumatology, Karolinska University Hospital, Stockholm, Sweden
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
Centre for Occupational and Environmental Medicine, Region Stockholm, Stockholm, Sweden
Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway

Institutions: Karolinska Institutet (Sweden); Jagiellonian University (Poland); Karolinska University Hospital (Sweden); Region Stockholm (Sweden); University of Bergen (Norway)

Journal: EBioMedicine, volume 129, article 106330

Dates: received 12 December 2025; accepted 28 May 2026; published online 16 June 2026; in print July 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1016/j.ebiom.2026.106330 · PMID 42302429 · PMCID PMC13292667 · OpenAlex W7164937320

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: genetics / omics (modality), human (organism), mouse (organism)

Methods: Statistics, Smoothing, state filtering, decompositions, Machine learning, Preprocessing, Connectivity, fMRI & imaging

Keywords: Juvenile idiopathic arthritis, Neuroinflammation, Oxidative stress, Biomarker, Collagen-induced arthritis, HMOX2

MeSH: Arthritis, Experimental*, Arthritis, Juvenile*, Hippocampus*, Neuroinflammatory Diseases*, Adolescent, Animals, Biomarkers, Child, Disease Models, Animal, Female, Humans, Inflammation, Male, Mice, Microglia, Oxidative Stress, Proteomics (* major topic)

Topic: Autoimmune and Inflammatory Disorders Research (Hematology, Medicine), according to OpenAlex

Funding: Stiftelsen Konung Gustaf V:s 80-årsfond (962319, 9877921); Reumatikerförbundet; Swedish Research Council (2021-02723); China Scholarship Council (202106380089)

Citations: not cited yet (Europe PMC); 56 references in the paper

Research resources: The mouse microglia cell line SimA9 RRID:CVCL_5I31

Abstract

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

bioproject:PRJNA1348353 — at NCBI BioProject; found in “Data sharing statement”

Data sharing statement

The raw RNA-sequencing data from mouse hippocampal tissues have been deposited in the Sequence Read Archive (SRA) under accession number PRJNA1348353 (https://ncbi.nlm.nih.gov/sra?term=PRJNA1348353). Other original data and materials are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 9 authors, 6 keywords, 17 MeSH terms, 4 funders, 56 references, 1 RRID.

Cite

This paper

Wen, X., Qu, H., Benedyk-Machaczka, M., Chen, D., Sundberg, E., Melén, E., Altman, M., Aulin, C., & Harris, H. E. (2026). Hippocampal neuroinflammation and altered peripheral neurobiological protein profile in experimental arthritis and systemic juvenile idiopathic arthritis. EBioMedicine, 129, 106330. https://doi.org/10.1016/j.ebiom.2026.106330

BibTeX

@article{wen2026hippocampal, author = {Wen, Xingzhao and Qu, Heshuang and Benedyk-Machaczka, Malgorzata and Chen, Daphne and Sundberg, Erik and Melén, Erik and Altman, Maria and Aulin, Cecilia and Harris, Helena Erlandsson}, title = {{Hippocampal neuroinflammation and altered peripheral neurobiological protein profile in experimental arthritis and systemic juvenile idiopathic arthritis}}, journal = {EBioMedicine}, year = {2026}, month = jun, volume = {129}, pages = {106330}, publisher = {Elsevier}, issn = {2352-3964}, doi = {10.1016/j.ebiom.2026.106330}, url = {https://doi.org/10.1016/j.ebiom.2026.106330}, pmid = {42302429}, pmcid = {PMC13292667} }

RIS

TY - JOUR AU - Wen, Xingzhao AU - Qu, Heshuang AU - Benedyk-Machaczka, Malgorzata AU - Chen, Daphne AU - Sundberg, Erik AU - Melén, Erik AU - Altman, Maria AU - Aulin, Cecilia AU - Harris, Helena Erlandsson TI - Hippocampal neuroinflammation and altered peripheral neurobiological protein profile in experimental arthritis and systemic juvenile idiopathic arthritis T2 - EBioMedicine J2 - eBioMedicine PY - 2026 DA - 2026/06/16 VL - 129 SP - 106330 SN - 2352-3964 PB - Elsevier DO - 10.1016/j.ebiom.2026.106330 UR - https://doi.org/10.1016/j.ebiom.2026.106330 LA - en ER -

CSL-JSON

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