The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: Inhibition of dendritic cell functions via Toll like receptor 9 signaling

Han, Jiaochan; Li, Xing; He, Juan; Huang, Xiaoyu; Zhou, Qing; Han, Yanping; Jie, Hongyu; Zhuang, Jian; Li, Yehao; Yang, Fengying; Zhai, Zeqing; Wu, Shufan; He, Yi; Yang, Bin; Sun, Erwei

doi:10.1016/j.biopha.2020.110848

Cited by 35 publications

(33 citation statements)

References 43 publications

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“…Considering the anti-cancer properties of HCQ, clinical studies have provided evidence for the repurposing of HCQ for use in cancer treatment. Approximately 30 clinical studies have evaluated the anticancer properties of HCQ in many cancer types with a combination of standard treatments [34]. Its roles in inhibiting autophagosome-lysosome fusion (LC3 cell marker, ATG5, and Beclin-1 expression) and reducing chemoresistance has gained considerable attention [37].…”

Section: Discussionmentioning

confidence: 99%

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Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis

Chen

Yadav

Chu

et al. 2021

Cancers

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Sorafenib is used for treating advanced hepatocellular carcinoma (HCC), but some patients acquire sorafenib resistance. We investigated the mechanisms underlying acquired sorafenib resistance in HCC cells and targeted them to re-sensitize them to sorafenib. In silico analysis indicated that toll-like receptor (TLR)-9 was significantly overexpressed, and that miRNA (hsa-miR-30a-5p) was downregulated in sorafenib-resistant HCC cells, which modulated HCC cell proliferation, oxidative stress, and apoptosis. TLR9 overexpression increased HCC cell proliferation, whereas TLR9 inhibition from hydroxychloroquine (HCQ) decreased HCC cell proliferation, tumor growth, oxidative stress marker (SOD1), and the formation of autophagosome bodies (reduced ATG5 and Beclin-1 expression). Moreover, HCQ treatment reduced epithelial–mesenchymal transition, leading to decreased clonogenicity, migratory ability, and invasiveness. HCQ targeted and reduced the self-renewal capacity phenotype by inhibiting tumorsphere generation. Both in vitro and in vivo results demonstrated the synergistic effect of the HCQ–sorafenib combination on sorafenib-resistant HCC (Huh7-SR) cells, increasing their sensitivity to treatment by modulating TLR9, autophagy (ATG5 and Beclin-1), oxidative stress (SOD1), and apoptosis (c-caspase3) expression and thus overcoming the drug resistance. This study’s findings indicate that TLR9 overexpression occurs in sorafenib-resistant HCC cells and that its downregulation aids HCC suppression. Moreover, HCQ treatment significantly increases sorafenib’s effect on sorafenib-resistant HCC cells.

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Section: Discussionmentioning

confidence: 99%

“…HCQ is a well-known antimalarial agent. It is a key inhibitor of TLR9 and is used in the treatment of cancer, especially for its anti-HCC effect [34], often combined with conventional anticancer drugs [34,35]. HCQ targets both cancer cells and the tumor microenvironment (TME) [36].…”

Section: Introductionmentioning

confidence: 99%

Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis

Chen

Yadav

Chu

et al. 2021

Cancers

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“…Likewise, TLR9 appears to be a possible target in RA as the TLR9 antagonist hydroxychloroquine halts the progression of RA by inhibiting dendritic cell (DC) maturation and migration from peripheral blood to the lymph nodes. Healthy DCs stimulated with serum from RA patients were treated with hydroxychloroquine, what led to lower expression of activation markers (i.e., CD86, CXCR4) and lower IFN-α secretion due to downregulation of TLR9 [ 27 ].…”

Section: Rheumatoid Arthritis (Ra)mentioning

confidence: 99%

Targeting Toll-like Receptor (TLR) Pathways in Inflammatory Arthritis: Two Better Than One?

Santos-Sierra

2021

Biomolecules

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Inflammatory arthritis is a cluster of diseases caused by unregulated activity of the immune system. The lost homeostasis is followed by the immune attack of one’s self, what damages healthy cells and tissues and leads to chronic inflammation of various tissues and organs (e.g., joints, lungs, heart, eyes). Different medications to control the excessive immune response are in use, however, drug resistances, flare-reactions and adverse effects to the current therapies are common in the affected patients. Thus, it is essential to broaden the spectrum of alternative treatments and to develop disease-modifying drugs. In the last 20 years, the involvement of the innate immune receptors TLRs in inflammatory arthritis has been widely investigated and targeting either the receptor itself or the proteins in the downstream signalling cascades has emerged as a promising therapeutic strategy. Yet, concerns about the use of pharmacological agents that inhibit TLR activity and may leave the host unprotected against invading pathogens and toxicity issues amid inhibition of downstream kinases crucial in various cellular functions have arisen. This review summarizes the existing knowledge on the role of TLRs in inflammatory arthritis; in addition, the likely druggable related targets and the developed inhibitors, and discusses the pros and cons of their potential clinical use.

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“…HCQ inhibits DC maturation and migration to lymph nodes, decreases CXCR4 expression and interferon-α secretion, and DC activation is involved in RA's pathogenesis. HCQ protects against RA by blocking TLR9 [88]. TARM1 is a member of the leukocyte immunoglobulin-like receptor family.…”

Section: Analysis Of Immune In Ltrating Cells That Play a Diagnostic mentioning

confidence: 99%

Identification of Key Immune-Related Genes, Molecular Pathways and Immune Infiltration as Diagnostic and Therapeutic Candidate Targets for RA: an integrated bioinformatics-based analysis

Fang

et al. 2021

Preprint

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Relevance Rheumatoid arthritis (RA) is a systemic autoimmune disease with an aggressive, chronic synovial inflammation as the main pathological change. However, the specific etiology, pathogenesis, and related biomarkers in diagnosis and treatment are still not fully elucidated. This study attempts to provide new perspectives and insights into RA at the genetic, molecular, and cellular levels through the tenet of personalized medicine. Methods Gene expression profiles of four individual knee synovial tissues were downloaded from a comprehensive gene expression database, R language was used to screen for significantly differentially expressed genes (DEGs), Gene Ontology Enrichment Analysis, Kyoto Gene Encyclopedia, and Gene Set Enrichment Analysis were performed to analyze the biological functions and signaling pathways of these DEGs, STRING online database was used to establish protein-protein interaction networks, Cytoscape software to obtain ten hub genes, Goplot to get six inflammatory immune-related hub genes, and CIBERSORT algorithm to impute immune infiltration. Results Molecular pathways that play important roles in RA were obtained: Toll-like receptors, AMPK, MAPK, TNF, FoxO, TGF-beta, PI3K and NF-κB pathways, Ten hub genes: Ccr1, Ccr2, Ccr5, Ccr7, Cxcl5, Cxcl6, Cxcl13, Ccl13, Adcy2, and Pnoc. among which Adcy2 and Pnoc have not been reported in RA studies, suggesting that they may be worthy targets for further study. It was also found that among the synoviocytes in RA, the proportions of plasma cells, CD8 T cells, follicular helper T cells, monocytes, γ delta T cells, and M0 macrophages were higher, while the proportions of CD4 memory resting T cells, regulatory T cells (Tregs), activated NK cells, resting dendritic cells, M1 macrophages, eosinophils, activated mast cells, resting mast cells were lower in proportion, and each cell played an important role in RA. Conclusions This study may help understand the key genes, molecular pathways, the role of inflammatory immune infiltrating cells in RA’s pathogenesis and provide new targets and ideas for the diagnosis and personalized treatment of RA.

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The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: Inhibition of dendritic cell functions via Toll like receptor 9 signaling

Cited by 35 publications

References 43 publications

Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis

Hydroxychloroquine (HCQ) Modulates Autophagy and Oxidative DNA Damage Stress in Hepatocellular Carcinoma to Overcome Sorafenib Resistance via TLR9/SOD1/hsa-miR-30a-5p/Beclin-1 Axis

Targeting Toll-like Receptor (TLR) Pathways in Inflammatory Arthritis: Two Better Than One?

Identification of Key Immune-Related Genes, Molecular Pathways and Immune Infiltration as Diagnostic and Therapeutic Candidate Targets for RA: an integrated bioinformatics-based analysis

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