Antigen-presenting cells orchestrate mixed inflammatory endotypes in atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by a complex pathogenesis involving aberrant activation of multiple immune responses. In recent years, targeted biologics have demonstrated significant efficacy in treating moderate to severe AD due to their precise mechanisms. However, the complex inflammatory profile of AD poses challenges for single-target biologics, leading to suboptimal therapeutic responses. By investigating the upstream induction mechanisms of mixed immune endotypes of AD, our study examined the roles of three types of skin antigen-presenting cells (APCs) in inducing distinct inflammatory responses in AD pathogenesis, utilizing animal models and genetically deficient mice. Our findings revealed that epidermal Langerhans cells primarily recognize allergens, induce Th2 inflammation, and promote IgE production. Nlrp3 contributes to macrophage activation by the AD lesion microbiota, driving Th17 inflammation and IgG1 production. The STING pathway facilitates dendritic cell activation, exacerbates the overall inflammatory process across mixed immune endotypes of AD, and the production of IgG2a and IgG1. In summary, our study conducted a comprehensive analysis of the upstream key antigen-presenting cells and their regulatory pathways that contribute to the progression of AD-associated immune endotypes. This research provides valuable insights into upstream mechanisms for controlling AD mixed inflammatory processes and offers strategic directions for developing combination therapies targeting multiple inflammatory pathways.