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Targeting the CCR6/CCL20 Axis in Entheseal and Cutaneous Inflammation
Author(s) -
Shi Zhenrui,
GarciaMelchor Emma,
Wu Xuesong,
Getschman Anthony E.,
Nguyen Mimi,
Rowland Douglas J.,
Wilson Machelle,
Sunzini Flavia,
Akbar Moeed,
Huynh Mindy,
Law Timothy,
Raychaudhuri Smriti K.,
Raychaudhuri Siba P.,
Volkman Brian F.,
Millar Neal L.,
Hwang Sam T.
Publication year - 2021
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41882
Subject(s) - ccl20 , c c chemokine receptor type 6 , enthesis , inflammation , stromal cell , chemokine , immunology , medicine , cancer research , pathology , chemokine receptor , tendon
Objective 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 from PsA patients and examined the presence of CCR6+ cells in synovial and tendon tissue. Utilizing an interleukin‐23 minicircle DNA (IL‐23 MC) mouse model exhibiting key features of both PsO and PsA, we investigated CCR6 and CCL20 expression as well as the preventive and therapeutic effect of CCL20 blockade. Healthy tendon stromal cells were stimulated in vitro with IL‐1β to assess the production of CCL20 by quantitative polymerase chain reaction and enzyme‐linked immunosorbent assay. The effect of conditioned media from stimulated tenocytes in inducing T cell migration was interrogated using a Transwell system. Results We observed an up‐regulation of both CCR6 and CCL20 in the enthesis of IL‐23 MC–treated mice, which was confirmed in human biopsy specimens. 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. Conclusion Our study highlights the pathogenic role of the CCR6/CCL20 axis in enthesitis and introduces the prospect of a novel therapeutic approach for treating patients with PsO and PsA.