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.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily affecting the joints [1] and a leading cause of disability in Western societies [2]
In mice in which inflammatory arthritis had been induced by K/BxN serum injection, we found a marked increase in plasma endotoxin concentrations when compared with naive mice (Figure 1A), in accordance with findings made in patients with arthritis [16]
In order to gain better insight into the mechanisms by which P. gingivalis regulated disease severity in inflammatory arthritis, we assessed whether the actions of P. gingivalis in promoting gut barrier breakdown were limited to arthritic mice or whether this occurred in healthy mice
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disease primarily affecting the joints [1] and a leading cause of disability in Western societies [2]. Environmental factors, such as mucosal barrier insults, are implicated in RA pathogenesis [3]. Current therapeutic strategies in RA are primarily aimed at mitigating the symptoms rather than treating the cause. Antirheumatic drugs need to be administered on a continuous basis to manage the symptoms, which leads to a number of unwanted side effects such as immunosuppression [6, 7] and inhibition of resolution and repair processes [8, 9]
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