Targeting the CCR6/CCL20 axis in entheseal and cutaneous inflammation

Objectives: To assess the involvement of the CCR6/CCL20 axis in psoriatic arthritis (PsA) and psoriasis (PsO) and to evaluate its potential as a therapeutic target. Methods: First, we quantified CCL20 levels in peripheral blood and synovial fluid of PsA patients and the presence of CCR6+ cells in synovial and tendon tissue. Utilizing an IL-23 minicircle DNA (MC) mouse model exhibiting key features of both PsO and PsA, we investigated CCR6 and CCL20 expression and the preventive and therapeutical effect of CCL20 blockade. Healthy tendon stromal cells were stimulated in vitro with IL-1β to assess the production of CCL20 by qPCR and ELISA. The effect of conditioned media from stimulated tenocytes in inducing T cell migration was interrogated with a transwell system. Results: We observed an upregulation of both CCR6 and CCL20 in the enthesis of IL-23 MC-treated mice, which was confirmed in human biopsies. Specific targeting of the CCR6/CCL20 axis with a CCL20 locked dimer (CCL20LD) blocked entheseal inflammation, leading to profound reductions in clinical and proinflammatory markers in the joints and skin of IL-23 MC-treated mice. The stromal compartment in the tendon was the main source of CCL20 in this model and accordingly, in vitro activated human tendon cells were able to produce this chemokine and to induce CCR6+ T cell migration, the latter of which could be blocked by CCL20LD. Conclusions: Our studies highlight the pathogenic role of CCR6-CCL20 axis in enthesitis and raise the prospect of a novel therapeutic approach for treating patients with PsO and PsA