HIF1α inhibition facilitates Leflunomide-AHR-CRP signaling to attenuate bone erosion in CRP-aberrant rheumatoid arthritis
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AbstractRheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive bone erosion. Leflunomide is originally developed to suppress inflammation via its metabolite A77 1726 to attenuate bone erosion. However, distinctive responsiveness to Leflunomide is observed among RA individuals. Here we show that Leflunomide exerts immunosuppression but limited efficacy in RA individuals distinguished by higher serum C-reactive protein (CRPHigher, CRPH), whereas the others with satisfactory responsiveness to Leflunomide show lower CRP (CRPLower, CRPL). CRP inhibition decreases bone erosion in arthritic rats. Besides the immunomodulation via A77 1726, Leflunomide itself induces AHR-ARNT interaction to inhibit hepatic CRP production and attenuate bone erosion in CRPL arthritic rats. Nevertheless, high CRP in CRPH rats upregulates HIF1α, which competes with AHR for ARNT association and interferes Leflunomide-AHR-CRP signaling. Hepatocyte-specific HIF1α deletion or a HIF1α inhibitor Acriflavine re-activates Leflunomide-AHR-CRP signaling to inhibit bone erosion. This study presents a precision medicine-based therapeutic strategy for RA.
All Author(s) ListLiang C, Li J, Lu C, Xie D, Liu J, Zhong C, Wu X, Dai R, Zhang H, Guan D, Guo B, He B, Li F, He X, Zhang W, Zhang BT, Zhang G, Lu A
Journal nameNature Communications
Detailed descriptionThe Erratum to this article has been published in Nature Communications 2020 11:1 - "This Article contained errors in Figs. 4i and 5a, for which the authors apologise. The lanes labelled ARNT (lower row) in Fig. 4i and HIF1alpha in Fig. 5a were not from the membranes used to probe for the other proteins shown in each panel. These have now been replaced with the correct rows from the same membranes. These errors were reproduced in the source data file that contains the uncropped membranes. The errors did not affect the conclusions of the manuscript. They have now been corrected both the PDF and HTML versions of the Article, and the Source Data file has been amended to include the correct images of the respective uncropped membranes."
Year2019
Month10
Day8
Volume Number10
Issue Number1
PublisherNature Publishing Group
Article number4579
ISSN2041-1723
LanguagesEnglish-United Kingdom

Last updated on 2021-23-07 at 23:54