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 TH17 and regulatory Treg 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.

Ccr6 Deficiency Attenuates Spontaneous Chronic Colitis in Winnie

“…This study has highlighted a functional role for CCR6 in the pathogenicity of spontaneous chronic colitis and provides evidence that CCR6 could be utilised as a functional therapeutic target in IBD. The proven functional efficacy in CCR6-inhibition in psoriasis, rheumatoid arthritis, multiple sclerosis carcinoma and EAE, could be replicated in IBD as well [11]. Recent research had shown the direct involvement of CCR6 with AKT/mTOR pathway which contributes to the TH17/Treg imbalance which is considered as the prime immunological factor which decides the resolution of colitis [21] and needs further investigation.…”

“…Not only colitis, but many other diseases relating to multi-organ pathologies are also influenced by the CCR6-CCL20 immune axis. Several autoimmune diseases such as experimental autoimmune encephalitis (EAE), rheumatoid arthritis (RA) and psoriasis have been shown to display reduced inflammation when CCR6 was inhibited in pre-clinical and clinical disease models [11]. Sixteen tractable CCR6 inhibitors have been introduced as a potential therapeutic option in those diseases [11].…”

“…Several autoimmune diseases such as experimental autoimmune encephalitis (EAE), rheumatoid arthritis (RA) and psoriasis have been shown to display reduced inflammation when CCR6 was inhibited in pre-clinical and clinical disease models [11]. Sixteen tractable CCR6 inhibitors have been introduced as a potential therapeutic option in those diseases [11]. In addition to having pathology within the gastro-intestinal tract, IBD patients also exhibit secondary organ pathologies termed as extraintestinal manifestations [12].…”

“…This led us to investigate the phenotype of the Ccr6-deficient Winnie mouse model and the influence of CCR6-CCL20 in multiple organs during the manifestation of colitis and its contribution towards initial molecular signalling. A plethora of therapies have been tried to date in the treatment of inflammatory bowel disease (IBD), however not, CCR6 -inhibition [11].…”

“…These results could then be translated into clinical trials which target the neutralization of CCR6 or its associated cytokines/products/mediators in human colitis. No such clinical trials have been performed with the existing CCR6 inhibitors up to date in IBD, which is also considered by some as an autoimmune disease [11].…”