Structural Investigation Into The CCL20 Locked Dimer and Its Therapeutic Use In Psoriatic Arthritis
Supported by Karen and Dale White Research Center of Excellence
Layman's Statement: The overall goal for this application is to use structural and biochemical techniques to develop and improve a new lead candidate for psoriasis and investigate the role of chemokine signaling in psoriatic arthritis. Chemokines are the bread crumbs of the body orchestrating the directed migration of immune cells. CCL20 is a skin specific chemokine that attracts T cells expressing its receptor CCR6. In psoriasis, these T cells produce other protein cytokines that lead to the typical psoriatic lesions of itchy, thickened and inflamed skin. I engineered a CCL20 locked dimer in a novel manner which reverses its pro-inflammatory signaling profile, blocks T cell homing and prevents psoriatic signs in a mouse model. The aim for this early career grant is to use structural and biochemical techniques to develop a better understanding of the CCL20 dimer - CCR6 relationship. This will set the groundwork for future directions to solve 3D structures of molecules important in regulating psoriatic diseases, like CCL20 and IL-23, and establish the role of CCL20/CCR6 in psoriatic arthritis. The expected outcomes from this project are new and improved molecules for helping patients and a clearer understanding of the mediators in these psoriatic diseases.
Grant Abstract: There is mounting evidence of a regulatory roll for IL-17 expressing cells in the inflammatory skin and joint diseases, psoriasis and psoriatic arthritis. T cells recruited to the skin and joints express the inflammatory cytokines IL-17A and IL-23 leading to pathological symptoms. Chemokines orchestrate cell migration in vivo and their dysregulation can lead to a variety of inflammatory diseases and cancer. Psoriatic lesions show elevated levels of the CC chemokine CCL20 and psoriasis patients have greater numbers of circulating T cells which express the CCL20-cognate receptor, CCR6. We and others have shown that T cells are drivers of psoriasislike signs in a CCR6-dependent manner in mice. Additionally, an engineered variant of CCL20 can block T cell migration and prevent skin inflammation in an IL-23 animal model of human psoriasis. Similar to psoriasis, psoriatic arthritis in humans is characterized by the synovial infiltration of IL-17 expressing CD4+ T cells resulting in enthesis and dactylitis. Additionally, anti-IL-17 neutralizing antibodies are effective treatments for alleviating disease symptoms. Since, CD4+ T cells can migrate to inflamed tissue in a CCR6-dependent manner, the chemokine axis CCL20/CCR6 may play a vital role in the development of psoriatic arthritis inflammation. Because of CCL20/CCR6’s clear role in psoriatic diseases, I propose to bridge basic and translational science to investigate chemokine-receptor interactions as a way to aid in developing new therapeutic leads for testing in state-of-the-art psoriatic animal models. In the immediate research aim, I propose to use NMR to dissect the CCL20LD-CCR6 interaction and to identify novel binding motifs as druggable hotspots. In the future directions, I propose to use X-ray crystallography, NMR, and computational techniques to construct a full structural model of the chemokine-receptor interaction and use the newly constructed models as templates for computational drug discovery. Additionally, I will investigate the role of CCL20/CCR6, due to its ability to regulate T cell migration, and test novel molecules (CCL20LD and others) in cutting edge models of psoriatic arthritis. This work will benefit basic and clinical scientists by providing new methods, tools and models for combating psoriatic diseases.