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

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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. Atopic dermatitis, also known as eczema, is a skin condition that causes patches that are itchy, red, and uncomfortable. Eczema can be difficult to treat because of the body’s complicated immune system, which becomes overactive and can lead to repeated flare-ups. An activating step, considered the inflammatory prequel, leads to an overactive immune system and occurs during the interaction of OX40 ligand and OX40, two signaling molecules that are found on immune cells. This interaction triggers the generation of more immune cells, the release of molecules that cause inflammation, and the formation of red, itchy patches on the skin. When the skin is disrupted, this can lead to damage and exposure to allergens that lead to further OX40 ligand/OX40 interactions, creating a cycle of OX40 ligand/OX40 interactions, inflammation, and skin damage. OX40 ligand/OX40 interactions can also train the immune system to remember this cycle, allowing it to happen more quickly in the future and contributing to flare-ups. New treatments are being developed to target this inflammatory prequel. These new treatments are designed to prevent OX40 ligand and OX40 from interacting, which could potentially help stop the cycle of inflammation and skin disruption. Clinical trials are testing these treatments in humans and have so far shown improvement of symptoms in patients with atopic dermatitis, with relief that continues even after stopping the treatment.