CCR6 as a possible therapeutic target in psoriasis

Abstract

Importance of the field: Psoriasis is a common, chronic autoimmune disease of the skin. Despite a number of effective treatments, new therapies are needed with enhanced efficacy, safety and convenience. Chemokine receptors are GPCRs that control leukocyte trafficking, and like other GPCRs, are good potential drug targets. The chemokine receptor CCR6 is expressed on the T(H)17 subset of CD4(+) T cells, which produces IL-17A/F, IL-22, TNF-alpha and other cytokines, and which has been implicated in the pathogenesis of psoriasis. CCR6 and its ligand, CCL20/MIP-3alpha, are highly expressed in psoriatic skin and CCR6 is necessary for the pathology induced in a mouse model of psoriasis-like inflammation.

Areas covered in this review: This review summarizes the evidence for the importance of the IL-23/T(H)17 axis, and in particular CCR6 and CCL20 in psoriasis, dating from 2000 to the present, and discusses the possibility of inhibiting CCR6 as a treatment for the disease.

What the reader will gain: The review informs the reader of the current thinking on the mechanisms of inflammation in psoriasis and the possible roles for CCR6 (and CCL20) in disease pathogenesis.

Take home message: We conclude that CCR6 should be investigated as a potential therapeutic target in psoriasis.

Figure 1. CCR6KO (Ccr6^−/−) mice are resistant to IL-23-induced acanthosis and dermal inflammation

Ears of wildtype (WT) control and CCR6KO mice were injected intradermally every other day for sixteen days with 20 μl PBS, either alone or containing 500 ng IL-23. (A) Ear thickness was measured on days between injections. Data points are means ± SEM from five experiments containing a total of at least thirty mice per group, *P < 0.01 vs. all other groups. (B) H&E-stained sections of PBS- or IL-23-injected ears from WT and CCR6KO mice at Day 15. (k), hyper-parakeratosis with intracorneal neutrophilic microabscess, (a), acanthosis, (b), increased proliferative activity of basal layer epidermal keratinocytes, (d), dermal lymphocytic infiltrate, and (v), telangiectasia of dermal blood vessels. Original magnification, 400×. Sections are representative of two experiments. Data are reproduced from: Hedrick MN, Lonsdorf AS, Shirakawa AK, Richard Lee CC, Liao F, Singh SP, et al. CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. J Clin Invest 2009 Aug;119(8):2317-29.