Deciphering Lipid-Mediated pH Regulation in the Stratum Corneum: Implications for Chronic Inflammatory Skin Diseases

• Applicant: Dr. Linda Li
• Subject Area: Dermatology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563181566

The stratum corneum (SC), the outermost layer of the skin, consists of dead, enucleated keratinocytes embedded in a lipid matrix. It serves as the primary barrier against environmental factors and plays a crucial role in maintaining skin homeostasis. Alterations in the SC, such as impaired barrier function or aberrant processes in keratinocyte differentiation, significantly contribute to the pathogenesis of chronic inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis. Recent evidence demonstrates that the SC is composed of three distinct pH zones: a weakly acidic lower zone, an acidic middle zone, and a neutral upper zone. This stepwise transition is essential for skin barrier functionality, regulation of enzymatic activities, and pathogen defense. However, the mechanisms driving this pH transition remain unknown. We hypothesize that specific lipids and their metabolism regulate the pH transition from the lower to the middle SC layer. Therefore, this project aims to investigate the role of lipids and their metabolic pathways in SC pH zone regulation and their implications for chronic inflammatory skin diseases. First, we will examine whether the three stepwise SC pH zones are preserved in various mouse models of inflammatory skin diseases (genetic AD models and the imiquimod-induced psoriasis model). Next, we will identify candidate lipids involved in the pH transition under physiological conditions and analyze their profiles in inflammatory skin diseases to assess similarities or alterations in relation to the observed SC pH zones. Based on these findings, we will investigate the metabolic pathways and enzymes involved in the metabolism of these candidate lipids and evaluate whether their inhibition affects the formation of SC pH zones. For clinical translation, we will examine whether the mechanisms identified in mouse models are applicable to human skin. To this end, we will analyze SC pH zones and lipid profiles in skin samples from healthy individuals and patients with AD and psoriasis to confirm the role of the identified key lipids in the pH transition between the lower and middle SC layers in humans. To achieve these objectives, we will employ cutting-edge techniques, including CRISPR/Cas9 technology, single-cell sequencing, lipidomics, and proteomics, to investigate the underlying processes in detail. The objective of this project is to identify lipid-based mechanisms contributing to the formation of the three SC pH zones, achieving a deeper understanding of SC homeostasis. This will provide new insights into skin barrier function and facilitate the development of therapeutic approaches, such as stratified emollients, for the treatment of barrier dysfunction in diseases like AD.

• DFG Programme: WBP Fellowship
• International Connection: Japan
• Host: Professor Dr. Masayuki Amagai