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Pro-inflammatory macrophages transporting gut-derived bacterial DNA drive autoimmune arthritis in spondyloarthropathy
Benjamin Cai, … , Anne-Sophie Bergot, Ranjeny Thomas
Benjamin Cai, … , Anne-Sophie Bergot, Ranjeny Thomas
Published July 31, 2025
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.188028.
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Research In-Press Preview Inflammation

Pro-inflammatory macrophages transporting gut-derived bacterial DNA drive autoimmune arthritis in spondyloarthropathy

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Abstract

Spondyloarthritis (SpA) is an inflammatory arthritis of the spine and joints associated with intestinal inflammation, in which it is hypothesized that innate immune exposure to entero-invasive species is followed by self/bacterial peptide presentation. However, the mechanisms underlying loss of tolerance to gut bacteria in genetically at-risk individuals are unclear. Curdlan (β-1,3-glucan, dectin-1 ligand)-treated ZAP-70W163C (SKG) mice develop autoimmune arthritis and ileitis associated with Gram-negative faecal dysbiosis. Using gnotobiotic mice, we show that curdlan-treated SKG mice mono-associated with Parabacteroides goldsteinii or Lactobacillus murinus developed ileitis, arthritis and enthesitis, while BALB/c mice were tolerant. Gnotobiotic SKG ileum upregulated Il23a and ER stress genes and lost goblet cells. Whereas bacterial DNA co-localised with neutrophils and inflammatory macrophages in SKG lamina propria, peri-articular bone marrow, entheses and spleen, in BALB/c bacterial DNA co-localised with resident macrophages in lamina propria and spleen. Human psoriatic-arthritis synovial tissue also contained cell-associated peri-vascular bacterial DNA. Curdlan-treated SKG spleen/bone marrow macrophages transferred severe arthritis and expanded Th17 cells in naïve SKG recipients, while BALB/c or germ free-SKG macrophages transferred mild arthritis and regulated Th17 cells. Thus, bacterial DNA and myeloid cells in the gut and their subsequent traffic regulate or enforce T cell pathogenicity in SpA.

Authors

Benjamin Cai, Rabina Giri, Amy J. Cameron, M. Arifur Rahman, Annabelle Small, Christopher Altmann, Yenkai Lim, Linda M. Rehaume, Mark Morrison, Mihir D. Wechalekar, Jakob Begun, Anne-Sophie Bergot, Ranjeny Thomas

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