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The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: Inhibition of dendritic cell functions via Toll like receptor 9 signaling - 18/11/20

Doi : 10.1016/j.biopha.2020.110848 
Jiaochan Han a, b, 1, Xing Li b, 1, Xiaoqing Luo b, Juan He c, Xuechan Huang d, Qingyou Zhou e, Yanping Han f, Hongyu Jie b, Jian Zhuang b, Yehao Li b, Fangyuan Yang b, Zeqing Zhai b, Shufan Wu b, Yi He a, b, , Bin Yang b, , Erwei Sun a, b,
a Department of Rheumatology and Immunology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, Guangdong, China 
b Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China 
c Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China 
d Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, Guangzhou, China 
e Department of Neurology, The Fifth Affiliated Hospital of Southern Medical University, Guangzhou, China 
f Clinical Lab, Hospital of South China Normal University, Guangzhou, China 

Corresponding authors at: Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, No. 183, Zhongshan Avenue West, Tianhe District, Guangzhou 510630, China.Department of Rheumatology and ImmunologyThe Third Affiliated HospitalSouthern Medical UniversityNo. 183, Zhongshan Avenue WestTianhe DistrictGuangzhou510630China⁎⁎Corresponding author at: Department of Rheumatology and Immunology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), No. 1 Jiazi Road, Lunjiao, Shunde District, Foshan, 528308, Guangdong, China.Department of Rheumatology and ImmunologyShunde HospitalSouthern Medical University (The First People's Hospital of Shunde)No. 1 Jiazi RoadLunjiaoShunde DistrictFoshanGuangdong528308China

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Graphical abstract

DCs act as sentinels for the immune system. DCs capture antigens locally and become mature, characterized by up-regulation of chemokine receptors (CCR7 and CXCR4), adhesion molecule (L-selectin), co-stimulator molecules (CD40, CD80 and CD86) and MHC II. Under high concentration of CCL21 in draining lymph nodes (LNs), mature DCs traffic to LNs via afferent lymph vessels and present antigens to T cells, resulting in the development of arthritis. HCQ impaires DC maturation via blocking TLR9 signaling, retrains DC migration to LNs, and prevents the initiation and progression of RA.




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Highlights

HCQ efficiently inhibited DC phenotypic and functional maturation stimulated by serum from RA patients.
HCQ prevented progression of arthritis by inhibiting DC maturation and migration from peripheral blood to LNs.
HCQ inhibited CpG ODN 1826-activated BMDC maturation and migration.
The effect of HCQ on DCs was related to the block in TLR9 signaling.
The development of arthritis was impaired in TLR9−/− mice.

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Abstract

Hydroxychloroquine (HCQ) is one of the most commonly prescribed immune-suppressants in treating rheumatoid arthritis (RA). Our previous research showed that HCQ suppressed RA development by inhibiting T follicular helper (Tfh) cells directly. Dendritic cells (DCs) serve as the link between innate and acquired immunity. Whether HCQ suppressed Tfh cell through DCs was not clear. In current study, we found that HCQ efficiently inhibited CD86, chemokine (C-X-C motif) receptor 4 (CXCR4) expression and interferon-α (IFN-α) secretion of healthy donor derived purified DCs stimulated by RA patient serum. To mimic RA, collagen-induced arthritis (CIA) mouse model was used and treated with HCQ daily for fifty-four days prior to sacrifice. We found HCQ inhibited DC maturation and migration to lymph nodes (LNs), manifested as down-regulated expression of CD40, CD80, CD86, MHCII (I-Aq) on LN DCs. In addition, HCQ reduced the level of chemokine receptor 7 (CCR7) and L-selectin on peripheral blood DCs and diminished percentage of LN DCs. Of note, HCQ only inhibited CpG ODN 1826-induced IL-12 secretion by bone marrow DCs (BMDCs) stimulated by various toll like receptor (TLR) agonists. Mechanistically, HCQ down-regulated the expression of TLR9 not only in healthy donor PBMC-derived DCs stimulated by RA patient serum, but also in LN DCs of CIA mice and CpG-activated BMDCs. Furthermore, arthritis scores in TLR9−/− mice were much lower than that in wild type mice with impaired maturity and migration capability of DCs. Collectively, activation of DCs contributes to the pathogenesis of RA and HCQ shows protective effects on RA by inhibition of DC activation via blocking TLR9.

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Keywords : Hydroxychloroquine, Rheumatoid arthritis, Dendritic cells, Toll like receptor 9


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© 2020  The Authors. Publicado por Elsevier Masson SAS. Todos los derechos reservados.
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