EGFR ligands synergistically increase IL‐17A‐induced expression of psoriasis signature genes in human keratinocytes via IκBζ and Bcl3

Abstract

Various epidermal growth factor receptor (EGFR) ligands are highly expressed in the epidermis of psoriasis lesions, and abnormal EGFR activation appears to be involved in the pathogenesis of psoriasis. However, how EGFR signaling contributes to the development of psoriasis is unclear. Interleukin (IL)‐17A, a critical effector of the IL‐23/IL‐17A pathway, increases the expression of psoriasis signature genes in keratinocytes and plays an essential role in the pathogenesis of psoriasis by inducing IκBζ, a critical transcriptional regulator in psoriasis. In this study, we stimulated primary human keratinocytes with IL‐17A and various EGFR ligands to investigate whether EGFR ligands regulate the expression of psoriasis signature genes. In cultured normal human keratinocytes and a living skin equivalent, EGFR ligands did not induce psoriasis‐related gene expression, but significantly enhanced the IL‐17A‐mediated induction of various psoriasis signature genes, including antimicrobial peptides, cytokines, and chemokines. This was dependent on an EGFR activation‐mediated synergistic increase in IL‐17A‐induced IκBζ expression and was partially mediated by the EGFR‐dependent upregulation of Bcl3. Therefore, EGFR ligands can act as synergistic agents of IL‐17A signaling by stimulating the epidermal production of psoriasis signature genes in psoriasis lesions. This study reveals a potential mechanism by which EGFR signaling contributes to the pathogenesis of psoriasis.

Nuclear IL-33 Plays an Important Role in EGFR-Mediated Keratinocyte Migration by Regulating the Activation of Signal Transducer and Activator of Transcription 3 and NF-κB

“…HB-EGF rapidly stimulated IL33 mRNA expression commencing 0.5 hours after addition and peaking (>5-fold) at 9 hours ( Figure 3 a) and significantly increased the protein levels of full-length IL-33 time dependently ( Figure 3 b). The IL33 mRNA level decreased sharply from 9 hours to 14 hours after HB-EGF treatment ( Figure 3 a), probably because EGFR signaling returned to the quiescent state after a long duration of stimulation ( Dai et al., 2022a ), and climbed slightly again at 23 hours ( Figure 3 a), which should be attributed to EGFR reactivation after autoinduction and cross-induction by epidermal GF family members ( Shirakata et al, 2010 ). Despite the increased IL-33 expression, HB-EGF stimulation could not exert IL-33 secretion ( Figure 3 c).…”

Transcriptome Analysis Identifies Biomarkers for the Diagnosis and Management of Psoriasis Complicated with Depression

“… 48 Although TGFA did not induce psoriasis-related gene expression, it could significantly enhance the IL-17A-mediated induction of various psoriasis signature genes, including antimicrobial peptides, cytokines, and chemokines. 49 Thus, TGFA production in psoriatic lesions may amplify the inflammation in the lesions. In depression, data regarding role of TGFA is lacking, however, it could be advantageous in supporting the neuroprotective effect in the CNS.…”

Portulaca oleracea L. extracts alleviate 2,4-dinitrochlorobenzene-induced atopic dermatitis in mice

“…Il-4, secreted by Th2 cells, is a cytokine closely related to the biological function of AD and continuously activate mast cells to produce more Ig E (44). It has been shown that elevated Th2 cytokines Il-4/Il-13 in AD lesions inhibit keratinocyte differentiation markers (FLG, LOR, keratin 1, and keratin 10) to impair skin barrier function (45). Accordingly, down-regulation of Il-4 expression is an important strategy for the treatment of AD.…”