Genes and Pathways Regulating Decline in Lung Function and Airway Remodeling in Asthma

Hur, Gyu Young; Broide, David H.

IL33 is a member of the IL-1 family that potently drives production of Th2 cytokines by Th2 cells, mast cells, basophils and ILC2. 65 IL33 is a ligand for IL1RL1 (also called ST2), an IL-1 family receptor. In mouse models, both IL33 and its ligand IL1RL1 induce airway inflammation, mucus production and airway remodeling. 66 At present no human studies have investigated whether IL33 or ILRL1 genetic variants are associated with features of airway remodeling in asthma. While both SNPs, for IL33 (rs1342326; P = 9 × 10 −10 ) and IL1RL1 (rs3771166; P = 3 × 10 −9 ), have significant associations with asthma, 40 there have been no studies demonstrating genetic associations between SNPs in IL33/IL1RL1 and lung function decline in asthma. , a disintegrin and metalloprotease domain 33; CHI3L1, chitinase 3-like 1 (same as YKL-40); CysLTs, cysteinyl leukotrienes; GSDMB, gasdermin B; IL1RL1, interleukin 1 receptor-like 1; IL, interleukin; ORMDL3, ORM1-like 3; PLAUR, plasminogen activator receptor, urokinase type; POSTN, periostin; TGF-β1/Smad-3, transforming growth factor beta 1/SMAD family member 3; TSLP, thymic stromal lymphopoietin; VEGF, vascular endothelial growth factor. *A-D includes a list of individual features of airway remodeling (smooth muscle hypertrophy/hyperplasia, peribronchial fibrosis, mucus metaplasia, and angiogenesis) and candidate mediators, cytokines that induce their remodeling.