Critical Role of Skin in Pathogenesis: Bidirectional Crosstalk Between Skin and Multiple Organs

ABSTRACT The skin, the largest organ in the human body, serves both as a mechanical barrier and an autonomous lymphoid organ, protecting against various environmental threats while maintaining the balance and functionality of multiple bodily systems. This relationship extends beyond the skin itself, involving other organs closely linked to skin homeostasis and related diseases. However, systematic reviews in this area are still lacking. This review seeks to explore this bidirectional communication, with a particular focus on the critical role of the immune system. We present a comprehensive review of the latest evidence, highlighting the fundamental roles of immune cells and cytokines within the skin–organ axis, particularly IL‐17A, which appears to interact with nearly all organs, illustrating their interplay and impact on skin health. Additionally, we discuss the implications of these interactions for the design and application of skin‐on‐a‐chip and organ‐on‐a‐chip technologies, emphasizing the importance of understanding these relationships for developing physiologically relevant in vitro models. By providing a comprehensive analysis of these complex interactions, this review establishes a solid theoretical foundation for the prevention, diagnosis, and treatment of diseases associated with the skin–organ axis, particularly regarding immune cells, cytokines, microorganisms, and their metabolites, ultimately aiming to advance research in related fields and offer new insights for clinical applications.