Project description:Although excessive exposure to UV is widely recognized as a major factor leading to skin perturbations and cancer, the complex mechanisms underlying inflammatory skin disorders resulting from UV exposure remain incompletely characterized. The nuclear hormone receptor PPARβ/δ is known to control cutaneous repair and UV-induced cancer development. Here, we describe a novel PPARβ/δ-dependent molecular cascade involving TGFβ-1 and miR-21-3p, which is activated in the epidermis in response to UV exposure. We establish that the passenger miRNA miR-21-3p, that we identify as a novel UV-induced miRNA in the epidermis, plays a pro-inflammatory function in keratinocytes, and that its high level of expression in human skin is associated with psoriasis and squamous cell carcinomas. Finally, we provide evidence that inhibition of miR-21-3p reduces UV-induced cutaneous inflammation in ex vivo human skin biopsies, thereby underlining the clinical relevance of miRNA-based topical therapies for cutaneous disorders.
Project description:Although excessive exposure to UV is widely recognized as a major factor leading to skin perturbations and cancer, the complex mechanisms underlying inflammatory skin disorders resulting from UV exposure remain incompletely characterized. The nuclear hormone receptor PPARβ/δ is known to control cutaneous repair and UV-induced cancer development. Here, we describe a novel PPARβ/δ-dependent molecular cascade involving TGFβ-1 and miR-21-3p, which is activated in the epidermis in response to UV exposure. We establish that the passenger miRNA miR-21-3p, that we identify as a novel UV-induced miRNA in the epidermis, plays a pro-inflammatory function in keratinocytes, and that its high level of expression in human skin is associated with psoriasis and squamous cell carcinomas. Finally, we provide evidence that inhibition of miR-21-3p reduces UV-induced cutaneous inflammation in ex vivo human skin biopsies, thereby underlining the clinical relevance of miRNA-based topical therapies for cutaneous disorders.
Project description:Although excessive exposure to UV is widely recognized as a major factor leading to skin perturbations and cancer, the complex mechanisms underlying inflammatory skin disorders resulting from UV exposure remain incompletely characterized. The nuclear hormone receptor PPARβ/δ is known to control cutaneous repair and UV-induced cancer development. Here, we describe a novel PPARβ/δ-dependent molecular cascade involving TGFβ-1 and miR-21-3p, which is activated in the epidermis in response to UV exposure. We establish that the passenger miRNA miR-21-3p, that we identify as a novel UV-induced miRNA in the epidermis, plays a pro-inflammatory function in keratinocytes, and that its high level of expression in human skin is associated with psoriasis and squamous cell carcinomas. Finally, we provide evidence that inhibition of miR-21-3p reduces UV-induced cutaneous inflammation in ex vivo human skin biopsies, thereby underlining the clinical relevance of miRNA-based topical therapies for cutaneous disorders.
Project description:Although excessive exposure to UV is widely recognized as a major factor leading to skin perturbations and cancer, the complex mechanisms underlying inflammatory skin disorders resulting from UV exposure remain incompletely characterized. The nuclear hormone receptor PPARβ/δ is known to control cutaneous repair and UV-induced cancer development. Here, we describe a novel PPARβ/δ-dependent molecular cascade involving TGFβ-1 and miR-21-3p, which is activated in the epidermis in response to UV exposure. We establish that the passenger miRNA miR-21-3p, that we identify as a novel UV-induced miRNA in the epidermis, plays a pro-inflammatory function in keratinocytes, and that its high level of expression in human skin is associated with psoriasis and squamous cell carcinomas. Finally, we provide evidence that inhibition of miR-21-3p reduces UV-induced cutaneous inflammation in ex vivo human skin biopsies, thereby underlining the clinical relevance of miRNA-based topical therapies for cutaneous disorders.
Project description:The role of PPARβ/δ in maintaining skin homeostasis during skin injury or inflammation has been widely studied. However, the majority of these reports based their studies in PPARβ/δ found in keratinocytes, which is the major cell type of the skin epidermis. The skin is mainy made up of the epidermis and dermis, and skin homeostasis is tightly regulated by complex crosstalks between epidermis and dermis. The dermis is predominantly made up of fibroblasts, and the predominant PPAR subtype in dermal fibroblasts is PPARβ/δ. Knowledge in the role of fibroblasts PPARβ/δ in skin homeostasis is lacking. To identify gene changes leading to phenotypical and biological functions alterations upon deletion of fibroblasts PPARβ/δ, we performed a comparative microarray gene expression analysis between Pparb/d^fl/fl and FSPCre-Pparb/d^fl/fl mice.
Project description:Psoriasis is a chronic inflammatory skin disease that is mediated by a complex crosstalk between immune cells and keratinocytes (KCs). Emerging studies showed a specific psoriatic microRNAs signature where miR-21 is one of the most upregulated miRNAs. In this study, we focused our investigations on the passenger miR-21-3p strand that is poorly studied in skin and in psoriasis pathogenesis. Here, we transfected the HaCaT cells with synthetic oligoncucleotides form of miR-21-3p and evaluated the impact of the over-expression of this miRNA in these call by RNA-seq analysis. We identified a network of differentially expressed genes involved in abnormal proliferation control and immune regulatory genes implicated in the molecular pathogenesis of psoriasis in response to miR-21-3p overexpression in KCs. These results were confirmed by functional assays that validate the proliferative potential of miR-21-3p. All these findings highlight the importance of miR-21-3p, an underestimated miRNA, in psoriasis and provide novel molecular targets for therapeutic purposes.