Specifically, we showed (1) Alternaria-driven release of IL-33 was attributable to a serine protease activity specific to this aeroallergen, (2) MMP-9 and MCPT-1 are novel downstream targets of IL-33, (3) the Alternaria intrinsic serine protease–IL-33 axis elicits a robust, rapid inflammation that may underlie the capacity of fungal proteases to act as TH2 adjuvants, and (4) the propensity of Alternaria serine protease activity to drive IL-33 release and ensuing inflammation rationalizes the clinical relevance of this aeroallergen at inducing severe rapid, onset asthma exacerbations. The gene discussed is IL33; the disease is asthma.