Thymic stromal lymphopoietin–Thymic stromal lymphopoietin receptor interface (TSLP–TSLPR interface)

The Thymic stromal lymphopoietin (TSLP)–Thymic stromal lymphopoietin receptor (TSLPR) protein-protein interaction interface is a critical molecular junction that initiates the inflammatory cascade in response to epithelial damage [1, 6]. TSLP is an alarmin cytokine produced by epithelial cells in the lungs, skin, and gastrointestinal tract when triggered by environmental insults such as allergens, viruses, or pollutants [11, 12]. The signaling mechanism requires TSLP to first bind with high affinity to the TSLPR subunit (also known as CRLF2), which subsequently recruits the interleukin-7 receptor alpha (IL-7Rα) chain to form a functional ternary complex [2, 10]. This assembly activates intracellular signaling through the JAK/STAT pathway, particularly involving JAK1, JAK2, STAT3, and STAT5, leading to the activation of dendritic cells, group 2 innate lymphoid cells (ILC2s), and Th2 cells [14, 18]. Dysregulation of this interface is strongly linked to the pathogenesis of type 2-driven diseases such as severe asthma, atopic dermatitis, and chronic rhinosinusitis with nasal polyps [1, 16]. Therapeutic intervention at this interface, most notably by the monoclonal antibody tezepelumab, prevents TSLP from binding to TSLPR, thereby inhibiting a broad range of downstream inflammatory biomarkers including eosinophils, IgE, and FeNO [11, 19]. Recent research has also identified small-molecule inhibitors, such as BP79, that specifically target this interface to provide novel treatment options for atopic diseases [4, 8].

Other names

TSLP:TSLPR interfaceTSLP-TSLPR complexSite I of the TSLP receptor complexThymic stromal lymphopoietin receptor-CRLF2 interfaceTSLP-CRLF2 interaction site

Blockade of the TSLP–TSLPR binding interface to prevent the assembly of the TSLP/TSLPR/IL-7Rα ternary complex, thereby inhibiting downstream JAK1/JAK2 and STAT3/STAT5 signaling pathways.