Abstract
Rheumatoid 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.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive bone erosion
We found that CRP upregulated Hypoxia-inducible factor 1α (HIF1α) expression, which competed with aryl hydrocarbon receptor (AHR) for AHR nuclear translocator (ARNT) association and interfered Leflunomide-AHR-CRP signaling in CRPH CIA rats
We showed that ACF decreased binding of ARNT with HIF1α and facilitated Leflunomide activating AHR to inhibit CRP production and attenuate bone erosion in CRPH CIA rats with no obvious toxicity
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive bone erosion. 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. Hepatocyte-specific HIF1α deletion or a HIF1α inhibitor Acriflavine re-activates Leflunomide-AHR-CRP signaling to inhibit bone erosion.
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