Suppressive effects of a novel CC chemokine receptor 4 antagonist on Th2 cell trafficking in ligand- and antigen-induced mouse models

Komiya, Takaki; Sugiyama, Tetsuya; Takeda, Kunio; Watanabe, Noriki; Imai, Masamichi; Kokubo, Mitsunori; Tokuda, Natsuko; Ochiai, Hiroshi; Habashita, Hiromu; Shibayama, Sotaro

doi:10.1016/j.ejphar.2013.10.006

Cited by 4 publications

(12 citation statements)

References 38 publications

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“…Our results also show that Th2 cells (CD4 + IL4 + ) from PBMCs and gingival tissues are similar with respect to chemokine receptor expression, being that CCR3, CCR4, and CCR8 are expressed by Th2 cells, suggesting that these three receptors contribute to Th2 cell migration to periodontal tissues along PD development. In accordance with our data, previous studies show a similar pattern of chemokine receptor expression by Th2 cells …”

Section: Discussionsupporting

confidence: 93%

“…Accordingly, our data show only a modest (<15%) decrease in IL‐4 levels in CCR8KO mice, suggesting that CCR3 and CCR4 receptors may compensate for the lack of CCR8 . Indeed, recent reports show that CCR3 inhibition impacts Th2 cell trafficking similarly to CCR4 blockade, reinforcing the involvement of multiple chemokine/chemokine receptors in Th2 response development . Another possibility is that the initial expression of IL‐4 is not dependent on the influx of polarized Th2 cells into periodontal tissues, and that the plasticity of T cells that reached the response site with a different phenotype (such as Th17 cells) could result in the initial IL‐4 production .…”

Section: Discussionsupporting

confidence: 52%

“…Conversely, CCL17 blockade neither significantly impaired the migration of Tregs, nor resulted in changes in the disease severity parameters. Accordingly, despite the sharing of CCR4 specificity/binding by CCL17 and CCL22, CCL17 seems to be less efficient in CCR4 + cells chemoattraction in vivo . Indeed, in vitro data shows that at similar concentrations CCL22 result in higher migration of CCR4 + cells than CCL17 (data not shown).…”

Section: Discussionmentioning

confidence: 91%

“…Accordingly, previous studies show a partial (∼50%) decrease of Th2 response in the absence of CCR4 . However, genetic or pharmacological ablation of CCR4 function results in controversial data regarding its role in the development of Th2‐type responses . Indeed, whereas the majority of research has centered on the role of CCR4 as a key CCR4 + cell chemoattractant, Th2 cells express a variety of chemokine receptors, such as CCR3, CCR8, and the DP2 or CRTH2 .…”

Section: Discussionmentioning

confidence: 99%

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IL-4/CCL22/CCR4 Axis Controls Regulatory T-Cell Migration That Suppresses Inflammatory Bone Loss in Murine Experimental Periodontitis

Araujo-Pires¹,

Vieira²,

Francisconi³

et al. 2014

Journal of Bone and Mineral Research

104

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Inflammatory bone resorption is a hallmark of periodontitis, and Tregs and Th2 cells are independently associated with disease progression attenuation. In this study, we employed an infection-triggered inflammatory osteolysis model to investigate the mechanisms underlying Treg and Th2 cell migration and the impact on disease outcome. Aggregatibacter actinomycetemcomitans–infected C57Bl/6 (wild-type [WT]) mice develop an intense inflammatory reaction and alveolar bone resorption, and Treg and Th2 cell migration is temporally associated with disease progression attenuation. Tregs extracted from the lesions preferentially express CCR4 and CCR8, whereas Th2 cells express CCR3, CCR4, and CCR8. The absence of CCR5 and CCR8 did not significantly impact the migration of Tregs and Th2 cells or affect the disease outcome. CCR4KO mice presented a minor reduction in Th2 cells in parallel with major impairment of Treg migration, which was associated with increased inflammatory bone loss and higher proinflammatory and osteoclastogenic cytokine levels. The blockade of the CCR4 ligand CCL22 in WT mice resulted in an increased inflammatory bone loss phenotype similar to that in the CCR4KO strain. Adoptive transfer of CCR4+ Tregs to the CCR4KO strain revert the increased disease phenotype to WT mice–like levels; also, the in situ production of CCL22 in the lesions is mandatory for Tregs migration and the consequent bone loss arrest. The local release of exogenous CCL22 provided by poly(lactic-co-glycolic acid) (PLGA) microparticles promotes migration of Tregs and disease arrest in the absence of endogenous CCL22 in the IL-4KO strain, characterized by the lack of endogenous CCL22 production, defective migration of Tregs, and exacerbated bone loss. In summary, our results show that the IL-4/CCL22/CCR4 axis is involved in the migration of Tregs to osteolytic lesion sites, and attenuates development of lesions by inhibiting inflammatory migration and the production of proinflammatory and osteoclastogenic mediators.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

IL-4/CCL22/CCR4 Axis Controls Regulatory T-Cell Migration That Suppresses Inflammatory Bone Loss in Murine Experimental Periodontitis

Araujo-Pires¹,

Vieira²,

Francisconi³

et al. 2014

Journal of Bone and Mineral Research

104

View full text Add to dashboard Cite

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“…CCR4 interactions with these major ligands are found to be associated in various mechanisms like recruitment of leukocytes in response to inflammatory signals [8] , homing and educating activated leukocytes [9] and also a plays a critical role in Treg migration and in metastasis of CCR4+ lymphoma cells and thereby can be an ideal target for treating cancer [10] . CCR4 is considered to be a novel therapeutic target as it is been considered as a preferential maker for T helper type2 (Th2) cells [11] . Th2 cells express CCR4+ positive cells which are been apparently involved in allergic airway inflammatory diseases [12] .…”

Section: Introductionmentioning

confidence: 99%

Homology Modeling of CCR 4: Novel Therapeutic Target and Preferential Maker for Th2 Cells

Shalini¹,

Madhavan²

2014

Journal of the Chosun Natural Science

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C-C chemokine receptor type 4 (CCR4) is a chemokine receptor with seven transmembrane helices and it belongs to the GPCR family. It plays an important role in asthma, lung disease, atopic dermatitis, allergic bronchopulmonary aspergillosis, cancer, inflammatory bowel disease, the mosquito-borne tropical diseases, such as dengue fever and allergic rhinitis. Because of its role in wide spectrum of disease processes, CCR4 is considered to be an important drug target. Three dimensional structure of the protein is essential to determine the functions. In the present study homology modeling of human CCR4 was performed based on crystal structure of CCR5 chemokine receptor. The generated models were validated using various parameters. Among the generated homology models the best one is selected based on validation result. The model can be used for performing further docking studies to identifying the critical interacting residues.

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Progress in pharmacological research of chemokine like factor 1 (CKLF1)

et al. 2018

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Suppressive effects of a novel CC chemokine receptor 4 antagonist on Th2 cell trafficking in ligand- and antigen-induced mouse models

Cited by 4 publications

References 38 publications

IL-4/CCL22/CCR4 Axis Controls Regulatory T-Cell Migration That Suppresses Inflammatory Bone Loss in Murine Experimental Periodontitis

IL-4/CCL22/CCR4 Axis Controls Regulatory T-Cell Migration That Suppresses Inflammatory Bone Loss in Murine Experimental Periodontitis

Homology Modeling of CCR 4: Novel Therapeutic Target and Preferential Maker for Th2 Cells

Progress in pharmacological research of chemokine like factor 1 (CKLF1)

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