HIF1α inhibition facilitates Leflunomide-AHR-CRP signaling to attenuate bone erosion in CRP-aberrant rheumatoid arthritis

Chao Liang, Jie Li, Cheng Lu, Duoli Xie, Jin Liu, Chuanxin Zhong, Xiaohao Wu, Rongchen Dai, Huarui Zhang, Daogang Guan, Baosheng Guo, Bing He, Fangfei Li, Xiaojuan He, Wandong Zhang, Bao-Ting Zhang, Ge Zhang () and Aiping Lu
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Chao Liang: Hong Kong Baptist University
Jie Li: Chinese University of Hong Kong
Cheng Lu: Hong Kong Baptist University
Duoli Xie: Hong Kong Baptist University
Jin Liu: Hong Kong Baptist University
Chuanxin Zhong: Hong Kong Baptist University
Xiaohao Wu: Hong Kong Baptist University
Rongchen Dai: Hong Kong Baptist University
Huarui Zhang: Hong Kong Baptist University
Daogang Guan: Hong Kong Baptist University
Baosheng Guo: Hong Kong Baptist University
Bing He: Hong Kong Baptist University
Fangfei Li: Hong Kong Baptist University
Xiaojuan He: Hong Kong Baptist University
Wandong Zhang: The First Affiliated Hospital of Anhui University of Chinese Medicine
Bao-Ting Zhang: Chinese University of Hong Kong
Ge Zhang: Hong Kong Baptist University
Aiping Lu: Hong Kong Baptist University

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12163-z

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