IL‐17 downregulates filaggrin and affects keratinocyte expression of genes associated with cellular adhesion

Abstract

Atopic eczema and psoriasis are common skin diseases. While it is well established that the pathogenesis of these diseases varies, both are characterized by impairment in epidermal barrier function and abnormal IL-17 expression in the skin and peripheral blood. Recent findings indicated that filaggrin is essential during barrier formation and its insufficiency underlies the pathogenesis of atopic eczema. Filaggrin downregulation has also been reported in psoriasis. It is clear that Th1 ⁄ Th2 bias influences expression of the protein, but an analysis of the effects of interleukin-17 (IL-17) on the expression of the protein and profilaggrin-processing enzymes has not yet been reported. In addition, the effect of the cytokine on components of functional epidermal barrier, tight junctions and adhesion ⁄ desmosomal proteins, has not been elucidated. Keratinocytes were exposed to interleukin-17A, and microarray analysis was performed. Filaggrin protein level was assessed by western blot. We have observed a significant decrease in profilaggrin mRNA level in interleukin-17A-exposed cultures (P = 0.008). Expression of processing enzymes was also altered, indicating an indirect effect of the cytokine on filaggrin production ⁄ degradation. Moreover, expression of many genes involved in cellular adhesion was also decreased. A significant downregulation of filaggrin at the protein level was detected by western blot in immortal and primary keratinocytes. Gene ontology analysis indicated changes in keratinization, epidermal differentiation and formation of the cornified envelope. We conclude that IL-17A downregulates the expression of filaggrin and genes important for cellular adhesion which could affect epidermal barrier formation. This effect potentially contributes to barrier dysfunction and could become a possible therapeutic target.

Epidermal tight junctions in health and disease

“…Numerous studies have demonstrated that several inflammatory mediators (e.g., IL4, IL13, IL25, IL17A and histamine) affect keratinocyte differentiation, most often leading to impaired barrier formation. [72][73][74][75] Studies on noncutaneous epithelium have established that inflammatory mediators are involved in TJ assembly and disassembly during inflammatory conditions, 76 and also in keratinocytes an influence of several cytokines on TJ proteins/function was described (see below). Whether these mediators directly affect epidermal TJs or whether it is an indirect effect via altered differentiation is an active area of research.…”

301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

“…1 and Supplementary Fig. S1) [16][17][18][19][20]30 . In agreement, we find that IL-17A interferes with differentiation and alters gene expression, which is completely blocked by Secukinumab (Supplementary Fig.…”

“…It is highly effective in the treatment of severe plaque psoriasis and psoriatic arthritis 14,15 . Expression studies revealed that IL-17 controls genes that encode for proteins associated with differentiation, with anti-microbial defense and with immune cell recruitment and activation, including filaggrin, S100A7, DEFB4, CCL20, and IL-8 (CXCL8) 16,17 . Many of these genes were confirmed when gene expression of psoriatic skin lesions was compared with control samples [18][19][20] .…”

Interleucina-17 como Alvo Terapêutico na Psoríase

“…75 Por outro lado, a IL-17 suprime a expressão de filagrina e de genes envolvidos na adesão dos queratinócitos, parecendo contribuir para a disrupção da barreira cutânea nas doenças inflamatórias da Revista Científica da Ordem dos Médicos www.actamedicaportuguesa.com pele. 76 Os efeitos da IL-17 estendem-se a outros tipos celulares cutâneos além dos queratinócitos, como as células dendríticas mielóides, os macrófagos, os fibroblastos ou as células endoteliais, potenciando as características inflamatórias observadas na psoríase.…”