The EGFR-ERK/JNK-CCL20 Pathway in Scratched Keratinocytes May Underpin Koebnerization in Psoriasis Patients

Abstract

Epidermal keratinocytes represent a rich source of C-C motif chemokine 20 (CCL20) and recruit CCR6+ interleukin (IL)-17A–producing T cells that are known to be pathogenic for psoriasis. A previous study revealed that scratch injury on keratinocytes upregulates CCL20 production, which is implicated in the Koebner phenomenon characteristically seen in psoriasis patients. However, the molecular mechanisms leading to scratch-induced CCL20 production remain elusive. In this study, we demonstrate that scratch injury upregulates the phosphorylation of epidermal growth factor receptor (EGFR) and that the specific EGFR inhibitor PD153035 attenuates scratch-induced CCL20 upregulation in an extracellular signal-related kinase (ERK)-dependent, and to a lesser extent, a c-Jun N-terminal kinase (JNK)-dependent but p38 mitogen-activated protein kinase (MAPK)–independent manner. Immunoreactive CCL20 was visualized in the keratinocytes that lined the scratched wound. IL-17A also induced the phosphorylation of EGFR and further augmented scratch-induced CCL20 upregulation. The EGFR-ERK/JNK-CCL20 pathway in scratched keratinocytes may explain why Koebnerization is frequently seen in psoriasis patients.

Interleukin-17A and Keratinocytes in Psoriasis

“…Other studies also underpin a possibility that IL-17A activates EGFR [98,181,182]. Chen et al have demonstrated that IL-17A transactivates EGFR in keratinocyte stem cells [98].…”

“…Although dermal dendritic cells and T cells express CCL20 in the psoriatic dermis [159], the expression of CCL20 is largely confined to the psoriatic epidermis, suggesting that epidermal keratinocytes are the major source of CCL20 production in psoriatic lesions [158,159]. CCL20 is constitutively expressed in cultured keratinocytes [201,204], and its production is upregulated by TNF-α and IL-17A [182,204]. Scratch injury upregulates the gene expression of CCL20, CXCL8, and IL36G, which may be related to the scratch-induced Koebner phenomenon frequently observed in patients with psoriasis [201].…”

Pathogenic implication of epidermal scratch injury in psoriasis and atopic dermatitis

“…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. [64][65][66][67] In addition, neutrophils are the first immune cells to infiltrate wounded sites, and appropriate neutrophilic recruitment is critical for efficient wound healing ( Fig.…”

“…2). 15,26,75,76 IL-17A directly stimulates keratinocyte proliferation (upregulation of Ki-67 and keratin 16), and induces abnormal keratinocyte differentiation by affecting the expression of transglutaminase 1, filaggrin and involucrin ( Fig. 2).…”

“…24 Recent studies have revealed that scratch injury to epidermal keratinocytes accelerates the release of chemokine (C-C motif) ligand 20 (CCL20) and CXCL8, which contribute to the recruitment of IL-17A-producing immune cells and neutrophils, respectively. 25,26 Scratch signals also stimulate keratinocytes to express IL-13 receptor a2 (IL-13Ra2), which is a decoy receptor for IL-13 that negatively regulates IL-13 signaling. 27 Meanwhile, scratch-induced IL-13Ra2 upregulation may enhance tissue fibrosis by binding to another IL-13Ra2 ligand, YKL-40.…”