Corrigendum
Open Access | 
10.1172/jci.insight.165600
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, and Costantino Pitzalis
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Published October 24, 2022 - More info
JCI Insight. 2022;7(20):e165600. https://doi.org/10.1172/jci.insight.165600.
© 2022 Flak et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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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
Original citation: JCI Insight. 2019;4(13):e125191. https://doi.org/10.1172/jci.insight.125191
Citation for this corrigendum: JCI Insight. 2022;7(20):e165600. https://doi.org/10.1172/jci.insight.165600
The authors recently became aware that representative illustrations presented in Figure 2A might be mistaken for original data. As this panel was used strictly for demonstrative purposes, it has been removed from the figure for clarity. The updated figure, figure legend, and description in the Results section are below.
Figure 2Arthritis dysregulates intestinal lipid mediator profiles. Arthritis was initiated by injection of K/BxN serum (50 μL per mouse, i.p.; days 0 and 2). On day 8, ilea were harvested from arthritic and naive mice and lipid mediators identified and quantified using lipid mediator profiling (see Methods for details). (A) MS/MS spectrum employed for the identification of RvD5n-3 DPA. Labeled ions are those matching assigned ion fragments for RvD5n-3 DPA. Inset, portion of the molecule that corresponds to each of the diagnostic ions; M, molecular mass. (B) Orthogonal partial least squares discriminant analysis (oPLS-DA) of intestinal lipid mediator profiles. Cumulative tissue concentrations for SPMs (i.e., arachidonic-, eicosapentaenoic acid–, n-3 docosapentaenoic– [DPA–], and docosahexaenoic acid–derived [DHA-derived] proresolving mediators) (C), RvDn-3 DPA (i.e., RvD1n-3 DPA, RvD2n-3 DPA, and RvD5n-3 DPA) (D), and RvD5n-3 DPA (E). Results for A are representative of n = 24 mice; for B are representative of n = 8 mice per group; for C–E are mean ± SEM for n = 8 mice per group from 2 independent experiments; *P ≤ 0.05 versus naive using Mann-Whitney U test. Results are expressed as pg/10 mg tissue.
