Loss of epidermal AP1 transcription factor function reduces filaggrin level, alters chemokine expression and produces an ichthyosis-related phenotype

Abstract

AP1 transcription factors are important controllers of epidermal differentiation. Multiple family members are expressed in the epidermis in a differentiation-dependent manner, where they function to regulate gene expression. To study the role of AP1 factor signaling, TAM67 (dominant-negative c-jun) was inducibly expressed in the suprabasal epidermis. The TAM67-positive epidermis displays keratinocyte hyperproliferation, hyperkeratosis and parakeratosis, delayed differentiation, extensive subdermal vasodilation, nuclear loricrin localization, tail and digit pseudoainhum and reduced filaggrin level. These changes are associated with increased levels of IFNγ, CCL3, CCL5, CXCL9, CXCL10, and CXCL11 (Th1-associated chemokines), and CCL1, CCL2, CCL5 and CCL11 (Th2-associated chemokines) in the epidermis and serum. S100A8 and S100A9 protein levels are also markedly elevated. These changes in epidermal chemokine level are associated with increased levels of the corresponding chemokine mRNA. The largest increases were observed for CXCL9, CXCL10, CXCL11, and S100A8 and S100A9. To assess the role of CXCL9, CXCL10, CXCL11, which bind to CXCR3, on phenotype development, we expressed TAM67 in CXCR3 knockout mice. Using a similar strategy, we examine the role of S100A8 and S100A9. Surprisingly, loss of CXCR3 or S100A8/A9 did not attenuate phenotype development. These studies suggest that interfering with epidermal AP1 factor signaling initiates a loss of barrier function leading to enhanced epidermal chemokine production, but that CXCR3 and S100A8/A9 do not mediate the phenotypic response.

c-FOS drives reversible basal to squamous cell carcinoma transition

“…Based on these encouraging results, we engineered a doxycycline-tamoxifeninducible Ras V12 (Kuonen et al, 2019) and a TGF-bR1-targeting short hairpin RNA (shRNA) (Figures S2D and S2E). Remarkably, RNA-seq profiles obtained upon Ras/MAPK activation and TGFb inhibition showed reduced enrichment of the cluster 3 signature and increased enrichment of the clusters 4 and 7 signature (Figures S2F and 2F), supporting the human relevance of our Appleford and Woollard, 2009;Folgueras et al, 2013;Fortunel et al, 2019;Gerdes et al, 2006;Hwang et al, 2008;Kadaja et al, 2014;Leishman et al, 2013;Li et al, 2019;Sastre-Perona et al, 2019;Soares and Zhou, 2018;Yang et al, 2015;Young et al, 2017). Looking specifically at the genomic proximity of differentially expressed genes upon BST induction (downregulated [DN] and upregulated [UP] genes; see Table S4), hair-follicle-related TF motifs such as Sox9 and Lhx showed reduced accessibility, mainly in the proximity of downregulated genes.…”

“…To identify the TF network controlling the dynamic chromatin landscape ( Li et al, 2019 ) associated with BST, we compared RNA-seq and assay for transposase-accessible chromatin using sequencing (ATAC-seq) changes upon Ras/MAPK and/or TGF-β inhibition ( Figures S2F and S3A ). Significant chromatin remodeling occurred in regions enriched with hair follicle and epidermal TF recognition motifs ( Figures 3A and S3B ) ( Adam et al, 2020 ; Appleford and Woollard, 2009 ; Folgueras et al, 2013 ; Fortunel et al, 2019 ; Gerdes et al, 2006 ; Hwang et al, 2008 ; Kadaja et al, 2014 ; Leishman et al, 2013 ; Li et al, 2019 ; Sastre-Perona et al, 2019 ; Soares and Zhou, 2018 ; Yang et al, 2015 ; Young et al, 2017 ). Looking specifically at the genomic proximity of differentially expressed genes upon BST induction (downregulated [DN] and upregulated [UP] genes; see Table S4 ), hair-follicle-related TF motifs such as Sox9 and Lhx showed reduced accessibility, mainly in the proximity of downregulated genes.…”

Oral Administration of ¥ Glucan and Lactobacillus plantarum Alleviates Atopic Dermatitis-Like Symptoms

“…TSLP was found to be overexpressed in both acute and chronic AD patients, and mouse AD models, and increased mRNA expression of IL-4, IL-13, and TNF-α [3,4]. The increased expression of these cytokines in turn triggers Th2-type reactions from dendritic cells [5], leading to decreased expression of filaggrin mRNA and subsequent damage to the skin barrier for the development of AD [6].…”

Therapeutic wavelengths of ultraviolet B radiation activate apoptotic, circadian rhythm, redox signalling and key canonical pathways in psoriatic epidermis

“…AP-1 transcription factors may play different roles in regulating differentiation, apoptosis and proliferation based upon epidermal location i.e. suprabasal and basal expression [ [54] , [55] , [56] ]. Furthermore, UV-induced AP-1 DNA binding and activation is dependent on cellular redox status [ 57 ].…”