Modulation of the CCR6-CCL20 Axis: A Potential Therapeutic Target in Inflammation and Cancer

Abstract

Prototypical functions of the chemokine receptor CCR6 include immune regulation by maneuvering cell chemotaxis and selective delimiting of the pro-inflammatory T_H17 and regulatory T_reg subsets during chronic or acute systemic inflammation. Inhibition of CCR6 is proposed to attenuate disease symptoms and promote recuperation of multiple inflammatory and autoimmune disorders. Prescription medicines with pharmacodynamics involving the inhibition of the chemokine axis CCR6⁻CCL20 are very limited. The development of such therapeutics is still at an early experimental stage and has mostly involved the utilization of pre-clinical models and neutralizing mono or polyclonal antibodies against either partner (CCR6 or CCL20). Other methods include the constitutive use of small molecules as peptide inhibitors or small interfering ribonucleic acid (siRNA) to interfere with transcription at the nuclear level. In our review, we aim to introduce the wide array of potential CCR6⁻CCL20 inhibitors with an emphasis on attendant immune-modulator capacity that have been tested in the research field to date and are immensely promising compounds as forerunners of future curatives. Sixteen different tractable inhibitors of the CCR6⁻CCL20 duo have been identified as possessing high medicinal potential by drug developers worldwide to treat autoimmune and inflammatory diseases as shown in Figure 1. A multitude of antibody preparations are already available in the current pharmaceutical market as patented treatments for diseases in which the CCR6⁻CCL20 axis is operative, yet they must be used only as supplements with existing routinely prescribed medication as they collectively produce adverse side effects. Novel inhibitors are needed to evaluate this invaluable therapeutic target which holds much promise in the research and development of complaisant remedies for inflammatory diseases.

Keywords: CCL20; CCR6; TH17; Treg; cancer; inflammatory diseases; inhibitors.

Figure 1

CCR6–CCL20 axis inhibitors investigated in pre-clinical and clinical studies to date as possible therapeutics for autoimmune and inflammatory diseases in multiple organ systems: nervous, skeletal, integumentary and gastrointestinal systems. CCR6 inhibitors are given above as a cluster, and CCL20 inhibitors are given below as a cluster. Legend: MAPK—mitogen activated protein kinase, p—protein, CCL20—CC chemokine ligand 20, mAbs—monoclonal antibodies, CCR6—CC chemokine receptor 6, hCCR6—humanised CCR6, Abs—antibodies, IL—interleukin, BET—bromodomain extraterminal proteins, R—receptor, MIR-150—micro ribonucleic acid-150, AOP-RANTES—amino oxypentane regulated on activation, normal T cell expressed and secreted.