CCR6 as a Potential Target for Therapeutic Antibodies for the Treatment of Inflammatory Diseases

Abstract

The CC chemokine receptor 6 (CCR6) is a G protein-coupled receptor (GPCR) involved in a wide range of biological processes. When CCR6 binds to its sole ligand CCL20, a signaling network is produced. This pathway is implicated in mechanisms related to many diseases, such as cancer, psoriasis, multiple sclerosis, HIV infection or rheumatoid arthritis. The CCR6/CCL20 axis plays a fundamental role in immune homeostasis and activation. Th17 cells express the CCR6 receptor and inflammatory cytokines, including IL-17, IL-21 and IL-22, which are involved in the spread of inflammatory response. The CCL20/CCR6 mechanism plays a crucial role in the recruitment of these pro-inflammatory cells to local tissues. To date, there are no drugs against CCR6 approved, and the development of small molecules against CCR6 is complicated due to the difficulty in screenings. This review highlights the potential as a therapeutic target of the CCR6 receptor in numerous diseases and the importance of the development of antibodies against CCR6 that could be a promising alternative to small molecules in the treatment of CCR6/CCL20 axis-related pathologies.

Keywords: CCR6; GPCRs; Th17 cells; antibody; immune system; inflammation; therapy.

Figure 1

(a) Cryo-EM structure of the human chemokine receptor CCR6 in complex with CCL20 and a Go protein (PDB ID: 6WWZ) colored by subunit. Wasilko et al. introduced the single-chain variable fragment (scFv16) in the complex to slow down the dissociation. (b) Snake helix box diagram depicts human CCR6 topology as seen from the side (GPCR database). Extracellular domains: purple; transmembrane domains: white; intracellular domains: blue.

Figure 2

The role of the CCR6 receptor in the immune response. Antigen-specific activation of naïve CD4⁺ T cells leads to the generation of Th17 and Treg cells mediated by the cytokine milieu and the transcription factors. Both cell types express CCR6 and have opposing functions in the immune system. The Th17/Treg balance plays a critically important role in many diseases. The CCR6 receptor is important to balance the pro-inflammatory, Th17, and anti-inflammatory, Treg, cell migration mediated by the CCL20 ligand secreted by Th17 cells. APC—antigen-presenting cells.