OX40 Ligand/OX40 Axis as the Inflammatory Prequel in Atopic Dermatitis: A Narrative Review

Atopic dermatitis is a complex and relapsing inflammatory skin disease attributed to skin barrier dysfunction and immune dysregulation. Because of the heterogeneous and unpredictable nature of the disease, moderate to severe atopic dermatitis remains challenging to treat, with a continued need for therapeutics capable of modulating multiple inflammatory pathways. Antigen-presenting cells (APCs) drive T cell activation through both primary and secondary signals. As part of the secondary, costimulatory signals, OX40 ligand (OX40L), expressed on activated APCs, binds the OX40 receptor expressed on T cells. The OX40L/OX40 signaling pathway is active during a dynamic phase of atopic dermatitis pathogenesis, representing the immune system's preparatory state that precedes the onset of the overt immune imbalance. During this critical period, defined here as the inflammatory prequel, OX40L/OX40 interactions promote T cell proliferation, survival, and cytokine production and release, therefore priming and amplifying inflammatory pathways central to atopic dermatitis pathogenesis and development of the disease. Sustained OX40L/OX40 signaling further promotes the generation of memory T cells and inhibits regulatory T cell function, contributing to chronic inflammation. Uniquely positioned at the crossroads of inflammatory pathways, OX40L/OX40 represents an alternative therapeutic target for atopic dermatitis and potentially other T cell-driven inflammatory diseases. Clinical trials evaluating antibodies targeting OX40L or OX40 are ongoing, with new evidence still emerging. Clinical studies have demonstrated efficacy in skin clearance and pruritus that persists beyond active treatment, supporting the role of this pathway in atopic dermatitis. Targeting the inflammatory prequel and intervening during the activation of the inflammatory cascade may therefore offer an opportunity to modulate immune dysregulation and achieve more sustained disease control in patients with atopic dermatitis.Graphical abstract available for this article.