Parasite-Derived IL-33 Inhibitors Prevent Bleomycin-Induced Lung Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive lung-scarring disease in which epithelial injury, consequent release of alarmins such as interleukin (IL)-33, and immune activation contribute to extracellular matrix deposition. The intestinal helminth Heligmosomoides polygyrus bakeri (Hpb) secretes immunomodulators that suppress type 2 immunity, including HpARI2, which binds IL-33, and HpBARI_Hom2, which blocks the IL-33 receptor ST2. Here, we test this parasite-derived dual blockade strategy in the bleomycin (BLM) mouse model, moving from live Hpb infection to administration of total Hpb excretory/secretory products (HES), and finally administering recombinant HpARI2 and HpBARI_Hom2 proteins. Hpb infection and HES treatment prevented BLM-induced lung fibrosis when administered during the early inflammatory phase. Recombinant HpARI2+HpBARI_Hom2 reproduced this protection, reduced collagen deposition and hydroxyproline accumulation, and dampened ILC2, eosinophil, macrophage, and neutrophil responses. In contrast, HES or HpARI2+HpBARI_Hom2 administration failed to reverse established fibrosis when administered later in the model. Similarly, administration of the IL-33trap fusion protein could replicate these effects, suppressing fibrosis when administered in the early inflammatory, but not later fibrotic phases of this model. These findings identify parasite-derived inhibition of the IL-33 axis as a defined molecular mechanism by which helminth products can prevent early inflammatory fibrogenesis, while also demonstrating that IL-33 blockade is unlikely to reverse established lung scarring.