The CCL20 and CCR6 axis in psoriasis

Abstract

Psoriasis is a TNF‐α/IL‐23/IL‐17A–mediated inflammatory skin disease that causes a significant socioeconomic burden in afflicted patients. IL‐17A–producing immune cells, including Th17 cells, are crucial effector cells in the development of psoriasis. IL‐17A stimulates epidermal keratinocytes to produce CCL20, which eventually recruits CCR6 + Th17 cells into the lesional skin. Thus, the CCL20/CCR6 axis works as a driving force that prepares an IL‐17A–rich cutaneous milieu. In this review, we summarize the current research topics on the CCL20/CCR6 axis and the therapeutic intervention of this axis for psoriasis.

Interleukin-17A and Keratinocytes in Psoriasis

“…In accordance with the accumulation of neutrophils in psoriasis, the gene expression of neutrophilic cytochemokines CXCL1, CXCL2, CXCL8, and IL-36 is upregulated in the lesional skin of psoriasis [68,[155][156][157]. Psoriatic keratinocytes produce a large amount of CCL20 [158,159], which is a potent chemoattractant for CCR6 + IL-17A-producing Th17 [89,143,160], ILC3 [161,162], Tc17 [163,164], and γδ T cells [78,165]. Interestingly, IL-17A actively upregulates the production of these key cytochemokines as well as proliferative capacity in keratinocytes.…”

Pathogenic implication of epidermal scratch injury in psoriasis and atopic dermatitis

“…58 While most chemokines redundantly bind to multiple receptors, CCL20 binds to CCR6 only, and thereby chemoattracts CCR6 + IL-17A-producing immune cells. [59][60][61] Human psoriatic epidermis abundantly expresses CCL20. 50,62,63 Epidermal keratinocytes are probably the main source of CCL20, in spite of the presence of CCL20 + dermal inflammatory cells, in the psoriatic lesions.…”

“…25 CCL20 is essential for the recruitment of IL-17A-producing immune cells, and CXCL8 and IL-36c are potent neutrophil chemoattractants. 15,25,60 Scratch-induced CCL20 upregulation is mediated by activation of epidermal growth factor receptor, extracellular signal-related kinase and partly by c-Jun N-terminal kinase. 26 These scratch injury-mediated reactions are very beneficial for physiological, coordinated wound healing in healthy individuals, because CXCL8, CCL20 and IL-17A accelerate epithelial wound healing.…”

CC chemokine receptor 6 (CCR6) in the pathogenesis of systemic lupus erythematosus

“…Serum CCL20 is also significantly higher in multiple sclerosis patients than healthy controls (HCs), reinforcing the role for the CCR6–CCL20 axis in this disease 17 . Finally, in psoriasis, keratinocytes secrete CCL20 which recruits CCR6 + pathogenic T H 17 cells to inflamed skin 18 . This has paved the way for novel therapeutics such as anti‐IL‐17 therapy for this condition, which has shown efficacy in randomized placebo‐controlled clinical trials 19 …”

“…17 Finally, in psoriasis, keratinocytes secrete CCL20 which recruits CCR6 + pathogenic T H 17 cells to inflamed skin. 18 This has paved the way for novel therapeutics such as anti-IL-17 therapy for this condition, which has shown efficacy in randomized placebo-controlled clinical trials. 19 Given the pleotropic effects of the CCR6-CCL20 chemokine axis and its role in autoimmunity, we examined its putative role in the classical systemic autoimmune disease, SLE.…”