The C-C Chemokines CCL17 and CCL22 and Their Receptor CCR4 in CNS Autoimmunity

Scheu, Stefanie; Ali, Shafaqat; Ruland, Christina; Arolt, Volker; Alferink, Judith

doi:10.3390/ijms18112306

Cited by 115 publications

(117 citation statements)

References 117 publications

(153 reference statements)

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“…CCL22 is a powerful chemoattractant for antigen-activated T cells, as well as monocytes, NK cells, and dendritic cells. 29 In this study, we only investigated the role of CCL17 and CCR4 in OLP, and the expression and biological functions of CCL22 in OLP remain to be further explored. In addition, since peripheral blood is non-specific to OLP, it is better to assess the expression of CCL17 and CCR4 in more specific body fluids such as salivary samples.…”

Section: Discussionmentioning

confidence: 99%

Potential roles of the CCL17‐CCR4 axis in immunopathogenesis of oral lichen planus

Shan

Shen

Fang

et al. 2019

J Oral Pathology Medicine

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Background: Oral lichen planus (OLP) is a T cell-mediated chronic inflammatory disease. C-C chemokine receptor type 4 (CCR4) and its cognate C-C motif chemokine ligand 17 (CCL17) play a key role in T-cell activation and trafficking, but their implication in OLP pathogenesis has not been explored. Our study was designed to analyze the expression and function of the CCL17-CCR4 axis in OLP. Methods:The mRNA expression levels of CCL17 and CCR4 in the circulating T cells of OLP subjects were examined by quantitative real-time PCR. The protein levels of CCL17 and CCR4 in the peripheral blood of OLP subjects were detected by enzyme-linked immunosorbent assay (ELISA) and Simple Western assay, respectively.The functional relevance of increased expression of CCL17 and CCR4 in OLP was demonstrated in proliferation, apoptosis, and migration assays. Results:The mRNA and protein expression levels of CCL17 and CCR4 in the peripheral blood of patients with OLP were significantly upregulated compared with those of controls. CCL17 induced the migration of OLP T cells. In addition, blocking CCR4 with a small molecule CCR4 antagonist not only inhibited the proliferation and migration of OLP T cells but also promoted the apoptosis of OLP T cells. Conclusion:Our findings indicate that the CCL17-CCR4 axis might be responsible for the inflammatory infiltration of T cells in OLP. K E Y W O R D SC-C chemokine receptor type 4, C-C motif chemokine ligand 17, oral lichen planus, T cells

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Section: Discussionmentioning

confidence: 99%

Potential roles of the CCL17‐CCR4 axis in immunopathogenesis of oral lichen planus

Shan

Shen

Fang

et al. 2019

J Oral Pathology Medicine

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“…Small molecule antagonists, like endogenous ligands, have also shown different ability to induce receptor internalization, which may be relevant to different biological effects. Some CCR4 antagonists combine with the allosteric site of CCR4, not the binding site of CCR4 to the ligand [102]. It may be for this reason that CCR4 antagonist compound 22 inhibits the Th1 and Th17 cell polarization as well as ameliorate EAE, but the CCR4 antagonist AF399 / 420/18025 had no significant impact on the clinical score of EAE [80,84].…”

Section: Ccr4 and Ccr6 Antagonistsmentioning

confidence: 99%

“…For example, in Phase I clinical trials, there was only one kind of CCR4 antagonists, GSK 2239633, as a possible treatment for asthma but still had no further development due to low bioavailability. This condition might be caused by complex pharmacology that has not been resolved, such as the CCR4 regulation on surface expression and transport aspects [102]. CCR4deficient mice(MOG induced in C57BL/6 mice) have been reported to exhibit low-grade EAE symptoms [33].…”

Section: Ccr4 and Ccr6 Antagonistsmentioning

confidence: 99%

“…First, the EAE priming phase: DC migrates to peripheral lymph nodes for self-antigen presentation, induces encephalitogenic Th cells. The second point is encephalitis Th cells are accumulated in the CNS to re-occur cognate antigen on local and CNS-invasive APC(antigen-presenting cells, homologous antigen) [102]. The pathological characteristics of experimental autoimmune encephalomyelitis are not uniform because they vary widely depending on the type of animal used and the type of epitope.…”

Section: Introductionmentioning

confidence: 99%

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The role of chemokines and chemokine receptors in multiple sclerosis

Cui

Chu

Chen

2020

International Immunopharmacology

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Multiple sclerosis (MS) is a chronic inflammatory disease that is characterized by leukocyte infiltration and subsequent axonal damage, demyelinating inflammation, and formation of sclerosing plaques in brain tissue. The results of various studies in patients indicate that autoimmunity and inflammation make an important impact on the pathogenesis of MS. Chemokines are key mediators of inflammation development and cell migration, mediating various immune cell responses, including chemotaxis and immune activation, and are important in immunity and inflammation, therefore we focus on chemokines and their receptors in multiple sclerosis. In this article, we summarize the study of the role of prominent chemokines and their receptors in MS patients and MS animal modelsand discuss their potential significance in inflammatory injury and repair of MS. We have also summarized the progress in the treatment of multiple sclerosis antagonists in recent years with chemokine receptors as targets.

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“…C-C chemokine receptor 4 (CCR4) is a high-affinity receptor for CCL17 and CCL22 that is elevated in inflamed tissues and plays a robust chemotactic role on activated T cells. 18 Although only a small fraction of naive Treg cells express CCR4, activated effector Treg cells residing in non-lymphoid tissues, such as skin and lungs, or peripheral activated effector Treg cells show enhanced expression of CCR4, 19 suggesting that CCR4 plays a dual role in directing activated effector T cells while recruiting Treg cells to the site of inflammation to maintain immune homeostasis. Indeed, CCR4-deficient Treg cells were unable to infiltrate localized tissue inflammation and failed to control immune responses in various models of inflammatory disease.…”

Section: C-c Chemokine Receptormentioning

confidence: 99%

Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

et al. 2019

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Summary Regulatory T (Treg) cells play a crucial role in maintaining self‐tolerance and resolution of immune responses by employing multifaceted immunoregulatory mechanisms. However, Treg cells readily infiltrate into the tumor microenvironment (TME) and dampen anti‐tumor immune responses, thereby becoming a barrier to effective cancer immunotherapy. There has been a substantial expansion in the development of novel immunotherapies targeting various inhibitory receptors (IRs), such as CTLA4, PD1 and LAG3, but these approaches have mechanistically focused on the elicitation of anti‐tumor responses. However, enhanced inflammation in the TME could also play a detrimental role by facilitating the recruitment, stability and function of Treg cells by up‐regulating chemokines that promote Treg cell migration, and/or increasing inhibitory cytokine production. Furthermore, IR blockade may enhance Treg cell function and survival, thereby serving as a resistance mechanism against effective immunotherapy. Given that Treg cells are comprised of functionally and phenotypically heterogeneous sub‐populations that may alter their characteristics in a context‐dependent manner, it is critical to identify unique molecular pathways that are preferentially used by intratumoral Treg cells. In this review, we discuss markers that serve to identify certain Treg cell subsets, distinguished by chemokine receptors, IRs and cytokines that facilitate their migration, stability and function in the TME. We also discuss how these Treg cell subsets correlate with the clinical outcome of patients with various types of cancer and how they may serve as potential TME‐specific targets for novel cancer immunotherapies.

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The C-C Chemokines CCL17 and CCL22 and Their Receptor CCR4 in CNS Autoimmunity

Cited by 115 publications

References 117 publications

Potential roles of the CCL17‐CCR4 axis in immunopathogenesis of oral lichen planus

Potential roles of the CCL17‐CCR4 axis in immunopathogenesis of oral lichen planus

The role of chemokines and chemokine receptors in multiple sclerosis

Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

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