TY - JOUR
T1 - HIF1α inhibition facilitates Leflunomide-AHR-CRP signaling to attenuate bone erosion in CRP-aberrant rheumatoid arthritis
AU - Liang, Chao
AU - Li, Jie
AU - Lu, Cheng
AU - Xie, Duoli
AU - Liu, Jin
AU - Zhong, Chuanxin
AU - Wu, Xiaohao
AU - Dai, Rongchen
AU - Zhang, Huarui
AU - Guan, Daogang
AU - Guo, Baosheng
AU - He, Bing
AU - Li, Fangfei
AU - He, Xiaojuan
AU - Zhang, Wandong
AU - Zhang, Bao Ting
AU - Zhang, Ge
AU - Lu, Aiping
N1 - Funding Information:
We thank technical staffs (Ms. Yeuk Siu Cheung and Mr. Chi Leung Chan) from Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University for providing technical support. This work was supported by the Ministry of Science and Technology of China (2013ZX09301307 to A.L.), the Hong Kong General Research Fund (HKBU479111 to G.Z., HKBU478312 to G.Z., HKBU262913 to G.Z., HKBU12102914 to G.Z., HKBU261113 to A.L., 12101018 to F.L., CUHK14112915 to B-T.Z. and CUHK489213 to B-T.Z.), the RC’s Start-up Grant for New Academics (162498 to C.L.) the Natural Science Foundation Council of China (81272045 to G.Z., 81700780 to C.L., 81703049 to F.L. and 81470072 to X.H.), the Research Grants Council and Natural Science Foundation Council of China (N_HKBU435/12 to G.Z.), the Croucher Foundation (Gnt#CAS14BU/CAS14201 to A.L.), the Interdisciplinary Research Matching Scheme (IRMS) of Hong Kong Baptist University (RC-IRMS/12-13/02 to A.L. and RC-IRMS/13-14/02 to G.Z.), the Hong Kong Baptist University Strategic Development Fund (SDF13-1209-P01 to A.L. and SDF15-0324-P02(b) to A.L.), the Hong Kong Research Grants Council Early Career Scheme (489213 to G.Z.), the Inter-institutional Collaborative Research Scheme of Hong Kong Baptist University (RC-ICRS/14-15/01 to G.Z. and RC-ICRS/16-17/01 to A.L.), the Faculty Research Grant of Hong Kong Baptist University (FRG1/13-14/024 to G.Z., FRG2/13-14/006 to G.Z. and FRG2/14-15/010 to G.Z.), the Science and Technology Innovation Commission of Shenzhen Municipality Funds (JCYJ20170307161659648 to F.L.), the China Academy of Chinese Medical Sciences (Z0252 and Z0293 to A.L.) and the National Key R&D Program of China (2018YFC1705205 to A.L. and 2018YFA0800804 to G.Z.).
Publisher copyright:
© The Author(s) 2019
PY - 2019/10/8
Y1 - 2019/10/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85073079397&partnerID=8YFLogxK
UR - https://doi.org/10.1038/s41467-020-16901-6
U2 - 10.1038/s41467-019-12163-z
DO - 10.1038/s41467-019-12163-z
M3 - Journal article
C2 - 31594926
AN - SCOPUS:85073079397
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
M1 - 4579
ER -