176 C10orf99/2610528A11Rik induces keratinocyte proinflammatory response and regulates lipid metabolism and barrier formation of the skin

Abstract

The protective machinery of the skin opposes external agents by barrier and innate and adaptive immunity. The local interplay in the epithelial-immune microenvironment (EIME) contributes to the situation-specific protective/inflammatory responses, and its dysregulation generates inflammatory loops in atopic dermatitis and psoriasis. Keratinocytes are the key player in the interplay and inflammatory loops in the EIME. However, a common regulator of keratinocyte response in this machinery has not yet been identified. To address this issue, we analyzed skin specimens from four animal models for atopic dermatitis by microarray. We found that expression levels of one orphan gene, 2610528A11Rik, were up in all the models. Protein expression levels of the human ortholog, C10orf99, were much higher in the lesional skin of atopic dermatitis or psoriasis than in healthy skin. RNA-Seq analyses of normal human epidermal keratinocytes (NHEKs) transfected with C10orf99-expressing plasmids revealed their increased proinflammatory transcriptional response, and gene ontology analyses suggested the highest relation to “Lipid/cholesterol biosynthesis,” “Cadherin/cell adhesion,” and “Mitochondrion.” Furthermore, transcription factor (TF) enrichment analysis found that only one pathway activating SREBP1, a TF regulating sterol synthesis, was significantly impaired in C10orf99-expressing NHEKs. Moreover, treatment of 3D-cultured human epidermis with C10orf99 synthetic peptides during its stratification downregulated the expression levels of filaggrin and loricrin in a dose-dependent manner. Our results suggest that 2610528A11Rik/C10orf99 can be a master regulator that induces keratinocyte protective response and regulates barrier formation of the skin.