Filaggrin and beyond New insights into the skin barrier in atopic dermatitis and allergic diseases, from genetics to therapeutic perspectives

Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide, affecting 20% of children and 5% of adults. One critical component in the pathophysiology of AD is the epidermal skin barrier, with its outermost layer, the stratum corneum (SC), conferring biochemical properties that enable resilience against environmental threats and maintain homeostasis. The skin barrier may be conceptualized as a key facilitator of complex interactions between genetics, host immunity, the cutaneous microbiome, and environmental exposures. The key genetic risk factor for AD development and persistence is a loss -of -function mutation in FLG, with recent advances in genomics focusing on rare variant discovery, establishment of pathogenic mechanisms, and exploration of the role of other epidermal differentiation complex gene variants in AD. Aberrant type 2 inflammatory responses down -regulate the transcription of key epidermal barrier genes, alter the composition of SC lipids, and induce further injury through a neurocutaneous feedback loop and the itch -scratch cycle. The dysbiotic epidermis exhibits reduced bacterial diversity and enhanced colonization with Staphylococcus and Malassezia species, which contribute to both direct barrier injury through the action of bacterial toxins and perpetuation of the inflammatory cascades. Enhanced understanding of each of the pathogenic mechanisms underpinning barrier disruption has led to the development of novel topical and systemic molecules, including interleukin (IL)-4Ra, IL -13, PDE4, and Janus -associated kinase inhibitors, whose clinical effectiveness exceeds conventional treatment modalities. In this narrative review, we aim to summarize the current understanding of the above -mentioned pathophysiological and therapeutic mechanisms, with a focus on the genetic, cellular, and molecular mechanisms underpinning AD development. (c) 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)