Defining the Roles of IL-33, Thymic Stromal Lymphopoietin, and IL-25 in Human Asthma

It is clear that a hyperactive type 2 immune response contributes to the pathogenesis of asthma in at least a subgroup of patients. Blood, sputum, and airway biomarkers of increased IL-13 activity (CLCA1, periostin, serpinB2, and MUC5AC) and IL-5 activity (eosinophilia) can identify those with a so-called “Th2-high” type of disease. The utility of molecular subtyping in asthma is buoyed by recent clinical trials demonstrating that some “TH2-high” asthmatics may respond favorably to therapies that block these pathways (1, 2). However, asthma is much more than a T cell–mediated disease, and innate epithelial and immune cell functions are critical in its pathogenesis (3). A better approach may to distinguish asthma subtypes based on the upstream innate factors that drive IL-13 and IL-5 production. In this context, three leading candidates have been identified in mouse models of airway disease (IL-33, thymic stromal lymphopoietin [TSLP], and IL-25), but their importance in the pathogenesis of human asthma has only recently been explored.