Skin-lung axis in the atopic march: The immune link from skin to lungs

The atopic march (AM) describes the sequential progression beginning with atopic dermatitis (AD), followed by the subsequent development of food allergy (FA), allergic asthma (AA), and allergic rhinitis (AR). The chronological characterization of AM is now widely recognized. However, the precise mechanisms leading to these atopic comorbidities after AD onset are not fully understood. Existing evidence suggests that skin barrier dysfunction constitutes a key initiating factor, promoting allergen sensitization and activation of immune responses. Recent studies have revealed that AM exhibits a trans-organ cascade effect, in which AD acts as an early event significantly increasing the risk of asthma development. This implicates a potential systemic link between the skin and lungs, termed the skin-lung axis. We propose the skin-lung axis as a pathway whereby cutaneous inflammation triggers pulmonary immune disorder. However, there remains a lack of a systematic overview regarding the mechanisms underlying this axis. Integrating multidimensional evidence encompassing genetic and epigenetic regulation, immune-inflammatory propagation, microbial-metabolic disturbance, and neuroimmune dysregulation, this review systematically explores the mechanistic role of the skin-lung axis in the AM. With the aim to elucidate how allergic inflammation originating in the skin remotely modulates the pulmonary microenvironment via multiple pathways, thereby facilitating asthma development, this review also discusses therapeutic strategies for preventing and intervening in AM progression.