CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in rheumatoid arthritis

Raemdonck, Katrien Van; Umar, Sadiq; Palasiewicz, Karol; Volkov, Suncica; Volin, Michael V.; Arami, Shiva; Chang, Helen; Zanotti, Brian; Sweiss, Nadera J.; Shahrara, Shiva

doi:10.1007/s00018-019-03235-w

Cited by 81 publications

(87 citation statements)

References 31 publications

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“…Li et al (20) found that arsenic trioxide improves the Treg/Th17 balance by modulating STAT3 in treatment-naïve RA patients. Previous studies have demonstrated that CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in RA (3). In the present study, the Treg/Th17 imbalance was confirmed to exacerbate the inflammatory responses in RA.…”

Section: Discussionsupporting

confidence: 79%

“…Previous studies have demonstrated a higher frequency of interleukin (IL)-17-producing Treg cells in the peripheral blood of RA patients compared with that in healthy subjects (2). Van et al (3) found that CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in RA. Therefore, the balance between Treg and Th17 cells plays a vital role in the pathogenesis of RA and could be a promising immunomodulatory drug target.…”

Section: Introductionmentioning

confidence: 99%

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Leonurine Regulates Treg/Th17 Balance to Attenuate Rheumatoid Arthritis Through Inhibition of TAZ Expression

Chen

Liu

et al. 2020

Front. Immunol.

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Leonurine, an active alkaloid extracted from Herba leonuri, is reported to have potent anti-inflammatory activity against rheumatoid arthritis (RA). However, the molecular mechanism of action of leonurine in RA remains poorly understood. In this study, we detected 3,425 mRNAs differentially expressed between CD4 + T cells of RA patients and those of healthy individuals using microarray raw data mining. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that transcriptional coactivator with PDZ-binding motif (TAZ) regulates a variety of biological processes including T-helper (Th)-17 cell development, and was thus selected for functional verification. In a naïve CD4 + T cell differentiation assay, we found that TAZ overexpression was associated with impaired balance between T regulatory (Treg) and Th17 cells in vitro. TAZ overexpression increased the levels of the pro-inflammatory cytokines interleukin (IL)-17, IL-1β, and tumor necrosis factor (TNF)-α and decreased that of the anti-inflammatory cytokine IL-10. Leonurine treatment had a direct recovery effect on the impaired balance and reduced the expression of TAZ and led to normalization of IL-17, IL-1β, and TNF-α and IL-10. Furthermore, IL-6 was found to promote the expression of TAZ and receptor activator of nuclear factor kappa-B ligand (RANKL), and RANK. Leonurine significantly inhibited TAZ-mediated expression of RANKL, and RANK and IL-6 in synovial fibroblasts. We conclude that the therapeutic effect of leonurine was through suppression of TAZ led to restoration of Treg/Th17 balance and suppression of synovial fibroblast action.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Leonurine Regulates Treg/Th17 Balance to Attenuate Rheumatoid Arthritis Through Inhibition of TAZ Expression

Chen

Liu

et al. 2020

Front. Immunol.

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“…Foamy phagocytes in the lesion center, containing abundant intracellular myelin remnants ( Fig. 1, A–D ), showed a more pronounced immunoreactivity for the inflammatory markers CCR7 ( Van Raemdonck et al, 2019 ), CD32 ( Kigerl et al, 2009 ), and IL-1B compared with foamy phagocytes in the lesion rim that contained less intracellular myelin ( Fig. 2, D–I ).…”

Section: Resultsmentioning

confidence: 99%

Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain

Bogie

Grajchen

Wouters

et al. 2020

Journal of Experimental Medicine

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Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype. This phenotypic shift was controlled by stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the desaturation of saturated fatty acids. Monounsaturated fatty acids generated by SCD1 reduced the surface abundance of the cholesterol efflux transporter ABCA1, which in turn promoted lipid accumulation and induced an inflammatory phagocyte phenotype. Pharmacological inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo. These findings identify SCD1 as a novel therapeutic target to promote remyelination.

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“…This infiltration in the synovial tissues is partially attributed to CCL21 and its receptor CCR7, where their blockage led to prevention of the migration. 68 It has been reported that plasma CCL19 level and monocyte CCR7 surface expression were higher in RA patients. 69,70 Likewise, CCL19 and CCL21 were reported to be higher in RA patients in comparison to osteoarthritis individuals.…”

Section: Chemokines In Rheumatoid Arthritismentioning

confidence: 97%

“…71 Moreover, CCL19 and CCL21 stimulated osteoclast migration as well as bone resorption by osteoclasts in an animal model of RA, 71 and CCL21 drives osteoclastogensis in RA through M1 macrophage polarization of Th17 cells as well as neovascularization. 68 CCL25 and its receptor CCR9 were both detected in the RA synovium. CCR9 was reported to be expressed on dendritic cells, macrophages, and fibroblast-like synoviocytes.…”

Section: Chemokines In Rheumatoid Arthritismentioning

confidence: 97%

<p>Role of Chemokines and Chemokine Receptors in Rheumatoid Arthritis</p>

Elemam¹,

Hannawi

Maghazachi³

2020

ITT

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Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases and a prototypic inflammatory disease, affecting the small joints of the hands and feet. Chemokines and chemokine receptors play a critical role in RA pathogenesis via immune cells recruitment. Several chemokines and chemokine receptors are abundant in the peripheral blood and in the local inflamed joints of RA. Furthermore, synthetic and biologics disease modifying anti rheumatic drugs have been reported to affect chemokines expression. Thus, many studies have focused on targeting chemokines and chemokine receptors, where some have shown positive promising results. However, most of the chemokine blockers in human trials of RA treatment displayed some failures that can be attributed to several reasons in their structures and binding affinities. Nevertheless, targeting chemokines will continue to be under development, in order to improve their therapeutic potentials in RA and other autoimmune diseases. In this review we provide an up-to-date knowledge regarding the role of chemokines and chemokine receptors in RA with an emphasis on their activities on immune cells. We also discussed the effects of drugs targeting those molecules in RA. This knowledge might provide impetus for developing new therapeutic modalities to treat this chronic disease.

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CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in rheumatoid arthritis

Cited by 81 publications

References 31 publications

Leonurine Regulates Treg/Th17 Balance to Attenuate Rheumatoid Arthritis Through Inhibition of TAZ Expression

Leonurine Regulates Treg/Th17 Balance to Attenuate Rheumatoid Arthritis Through Inhibition of TAZ Expression

Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain

<p>Role of Chemokines and Chemokine Receptors in Rheumatoid Arthritis</p>

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