CE9A215 (inotodiol) ameliorates oxazolone-induced atopic dermatitis by targeting mast cells and proinflammatory cytokines.

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disorder requiring long-term management; however, current therapeutics are often limited by side effects. CE9A215 (inotodiol), recently identified as a selective liver X receptor β agonist, has shown potential for regulating inflammation with a favorable safety profile. This study investigated the therapeutic efficacy and underlying mechanisms of CE9A215 in a murine model of oxazolone-induced chronic AD. We evaluated cellular responses using human mast cells (LUVA) and macrophages (RAW264.7) and assessed in vivo efficacy after oral administration of CE9A215 (4 and 10 mg/kg) for 9 days. In vitro, CE9A215 inhibited mast cell degranulation more effectively than dexamethasone and significantly suppressed lipopolysaccharide-induced proinflammatory cytokine production in macrophages. In vivo, CE9A215 treatment markedly ameliorated AD-like clinical symptoms, reducing epidermal hyperplasia to levels comparable to dexamethasone. Mechanistically, CE9A215 stabilized mast cells and macrophages within the dorsal skin, leading to significantly reduced levels of β-chymase in both serum and tissue. Furthermore, it downregulated the expression of key proinflammatory cytokines (tumor necrosis factor α and interleukin-1β) and T helper 2-associated cytokines (interleukin-4) in skin lesions. Notably, although systemic total IgE levels remained unchanged, the specific suppression of cutaneous interleukin-4 and inflammatory mediators indicates targeted regulation of the local inflammatory cascade. These findings suggest that CE9A215 alleviates AD pathology through liver X receptor β-mediated stabilization of mast cells and immune modulation, positioning it as a promising therapeutic candidate for chronic AD. SIGNIFICANCE STATEMENT: Current therapies for atopic dermatitis, including corticosteroids, are often limited by long-term side effects. This study identifies CE9A215 (inotodiol) as a potent therapeutic agent that ameliorates chronic atopic dermatitis pathology by targeting liver X receptor β. Unlike nonselective liver X receptor agonists known to induce hepatic steatosis, CE9A215 selectively stabilizes mast cells and macrophages without systemic toxicity.