Abstract
Lung-trafficking helminth larvae drive an early pulmonary neutrophilic inflammation prior to the establishment of the hallmark Type 2 immune response. While IL-11 is known to play crucial roles in chronic inflammatory responses, its role in the mucosal immunity to helminth parasites has not been assessed to date. In a mouse model for Ascaris infection, we observed elevated IL-11 levels in lung tissue that strikingly correlated with parasite burden. Single-cell molecular and phenotypic analyses, combined with confocal and RNAscope spatial imaging, identified lung epithelial cells and peribronchial stromal cells, including myofibroblasts and smooth muscle cells, as important sources of IL-11 in naïve and Ascaris-infected lungs. In the absence of IL-11 signaling, using IL-11Rα1-deficient mice infected with Ascaris, we noted a marked reduction in lung neutrophil influx and decreased levels of neutrophil-associated mediators (CXCL-1 and G-CSF). Conversely, intranasal administration of recombinant IL-11 induced high levels of G-CSF and CXCL-1 and enhanced mucosal inflammation in the lungs. To confirm direct effect of IL-11 in regulating neutrophil-associated markers we showed that in vitro stimulation with recombinant IL-11 drove IL-6 and G-CSF production in fibroblasts, and CXCL-1 in epithelial cells. These findings suggest that IL-11 acts as a pro-inflammatory mediator that orchestrates the early neutrophil-driven inflammation during acute helminth infection, unraveling a critical role of IL-11 in pathogenic inflammatory responses.