Structural and functional consequences of IL33 and IL1RL1 coding variants on IL-33/ST2 signaling

Interleukin-33 (IL-33) is a central regulator of immune responses and inflammation, and genetic variation in IL33 and its receptor IL1RL1 (ST2) is strongly linked to disease susceptibility, notably asthma. Emerging evidence suggests that IL-33 also influences hematopoietic processes and platelet biology, indicating functions beyond canonical immunity. We investigated two missense variants identified in a patient with unexplained thrombocytopenia: IL33 c.385T>C (p.Tyr129His) and IL1RL1 c.1501_1502CA>AG (p.Gln501Arg). Structural modeling revealed that IL-33 Y129H disrupts a conserved hydrogen bond within the IL-33/ST2/IL-1RAcP ternary complex, destabilizing receptor engagement. Functional assays confirmed markedly reduced biological activity, establishing Y129H as a loss-of-function variant. The IL1RL1 Q501R variant affects the Toll/IL-1 receptor (TIR) domain, critical for recruiting adaptor proteins such as MyD88. Modeling revealed pronounced perturbation in a peripheral helix of the TIR domain, likely impacting adaptor recruitment and downstream signaling, providing a mechanistic explanation for its association with reduced asthma risk. Together, we provide structural and mechanistic insights into these clinically relevant IL33 and IL1RL1 variants and demonstrate that they jointly impair IL-33/ST2 signaling. Their simultaneous occurrence in a patient with thrombocytopenia highlights a potential role for this pathway in platelet homeostasis and stress-responsive hematopoiesis.