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

Abstract

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

Lichen Planus

“…Several alterations in the expression of cytokines and chemokines in lesions or serum of patients with LP have been described. Serum levels of interleukin (IL)-5, IL-6, IL-8, IL-9, IL-10, IL-12 IL-17, IL-22, tumor necrosis factor-α, transforming growth factor-β, interferon (IFN)-γ, CXCR-3, CXCR-4, CXCL-10, CXCL-12, CCR1, CCR3, CCR4, CCL5-CCR5, and CCL17-CCR4) have been found elevated (80)(81)(82)(83)(84)(85)(86)(87)(88)(89). In addition, an increased expression IFN-γ and IL-17 in the skin of LP lesions has been described (81,90)-albeit some other studies refuted these observations (91).…”

FAP‐α+ immunofibroblasts in oral lichen planus promote CD4+ T‐cell infiltration via CCL5 secretion

“…T cell-mediated immune disorders involve various cytokines, among which chemokines play an important role in the pathogenesis of OLP. 7,14,34 Chemokines can mediate inflammatory cell chemotaxis, immune cell activation and response, tumor growth and metastasis. 35 The chemokine CCL5, also known as RANTES, can be synthesised and secreted by platelets, CD8 + T cells, endothelial cells, macrophages, endothelial cells and fibroblasts.…”

“…Erosive OLP (EOLP) is characterized by hyperaemia, erosions and ulcers around white lesions, reflecting a more severe disease phase. Patients may experience irritating and spontaneous pain 6,7 …”

“…Previous studies have demonstrated that immune reactions and cytokines play dominant roles in the pathogenesis of OLP. Many inflammatory factors exist in the local microenvironment of OLP, such as interleukins (IL‐6, IL‐8, IL‐2, IL‐4 and IL‐17), TNF‐α 11,12 and chemokines (CXCL10, CCL17, CCL5 and CXCL12) 7,13–15 . Furthermore, immune cells, endothelial cells, fibroblasts and the extracellular matrix constitute the local pathological microenvironment.…”

Reveals of quercetin’s therapeutic effects on oral lichen planus based on network pharmacology approach and experimental validation

“…Immune imbalance has an important role in the pathogenesis of OLP 6 , 7 , and involves multiple biological processes, signaling pathways and cytokines. Darczuk et al indicated that free radicals and increased oxidative stress might be involved in the occurrence and development of OLP lesions 8 .…”