Inflammatory arthritis disrupts gut resolution mechanisms, promoting barrier breakdown by Porphyromonas gingivalis
Magdalena B. Flak, Romain A. Colas, Estefanía Muñoz-Atienza, Michael A. Curtis, Jesmond Dalli, Costantino Pitzalis
Magdalena B. Flak, Romain A. Colas, Estefanía Muñoz-Atienza, Michael A. Curtis, Jesmond Dalli, Costantino Pitzalis
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Research Article Immunology Inflammation

Inflammatory arthritis disrupts gut resolution mechanisms, promoting barrier breakdown by Porphyromonas gingivalis

Abstract

Rheumatoid arthritis is linked with altered host immune responses and severe joint destruction. Recent evidence suggests that loss of gut homeostasis and barrier breach by pathobionts, including Porphyromonas gingivalis, may influence disease severity. The mechanism(s) leading to altered gut homeostasis and barrier breakdown in inflammatory arthritis are poorly understood. In the present study, we found a significant reduction in intestinal concentrations of several proresolving mediators during inflammatory arthritis, including downregulation of the gut-protective mediator resolvin D5n-3 DPA (RvD5n-3 DPA). This was linked with increased metabolism of RvD5n-3 DPA to its inactive 17-oxo metabolite. We also found downregulation of IL-10 expression in the gut of arthritic mice that was coupled with a reduction in IL-10 and IL-10 receptor (IL-10R) in lamina propria macrophages. These changes were linked with a decrease in the number of mucus-producing goblet cells and tight junction molecule expression in the intestinal epithelium of arthritic mice when compared with naive mice. P. gingivalis inoculation further downregulated intestinal RvD5n-3 DPA and Il-10 levels and the expression of gut tight junction proteins. RvD5n-3 DPA, but not its metabolite 17-oxo-RvD5n-3 DPA, increased the expression of both IL-10 and IL-10R in macrophages via the upregulation of the aryl hydrocarbon receptor agonist l-kynurenine. Administration of RvD5n-3 DPA to arthritic P. gingivalis–inoculated mice increased intestinal Il-10 expression, restored gut barrier function, and reduced joint inflammation. Together, these findings uncover mechanisms in the pathogenesis of rheumatoid arthritis, where disruption of the gut RvD5n-3 DPA–IL-10 axis weakens the gut barrier, which becomes permissive to the pathogenic actions of the pathobiont P. gingivalis.

Authors

Magdalena B. Flak, Romain A. Colas, Estefanía Muñoz-Atienza, Michael A. Curtis, Jesmond Dalli, Costantino Pitzalis

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Figure 1

Inoculation of arthritic but not naive mice with P. gingivalis promotes gut barrier breakdown.

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Inoculation of arthritic but not naive mice with P. gingivalis promotes ...
(A–C) Mice were inoculated with P. gingivalis (109 CFU per mouse) or given vehicle (PBS) on days –1, 1, and 3 and injected with K/BxN serum (50 μL per mouse, i.p.; days 0 and 2). Tissues were harvested on day 8 after K/BxN administration, and (A) plasma endotoxin concentrations were determined. (B) Gene expression of tight junction protein Tjp1 and antimicrobial Lyz1. Results for A and B are mean ± SEM. n = 3–4 mice per group from 2 independent experiments. *P < 0.05 using Kruskall-Wallis test followed by Dunn’s post hoc test. (C) Representative images of E-cadherin staining in arthritic mice (K/BxN) inoculated with or without P. gingivalis (scale bars: 25 μm). Results are presented as mean ± SEM. n = 4 mice per group from 2 independent experiments. (D) Mice were gavaged with P. gingivalis (109 CFU, days –1, 1, 3) or vehicle. 16S rRNA gene levels were measured by 16S qPCR in mesenteric lymph nodes (MLNs), spleens, and livers of naive control mice or P. gingivalis–inoculated mice (Naive + P. gingivalis) to assess breach of bacteria across the gut barrier. Results are mean ± SEM for n = 3 mice per group; unpaired t test with Welch’s correction. (E) Representative images of E-cadherin (red) and DAPI staining (blue) of ileal tissue from naive mice or P. gingivalis–inoculated mice (Naive + P. gingivalis). Representative of n = 4 mice from 2 independent experiments. Scale bars: 25 μm. (F) Gene expression levels of intestinal epithelium–secreted antimicrobial Lyz1 and cytokines Il17a, Tgfb, and Il10 in intestines of naive and nonarthritic P. gingivalis–inoculated (Naive + P. gingivalis) mice. Results are mean ± SEM for n = 3 mice per group.