Abstract
Tissue infiltration by circulating monocytes is a critical step in the initiation and augmentation of type 2 inflammatory responses in the lungs. Our studies demonstrate that IL-33-/- mice have a defect in monocyte extravasation from the vasculature to the lung interstitium during induction of type 2 inflammatory responses. This result suggests that monocyte migration to the lungs is IL-33 dependent, and we found that administration of exogenous recombinant IL-33 is sufficient to restore monocyte localization to the lung interstitium. Further investigation of the effect of early administration of recombinant IL-33 on the lungs identified upregulation of multiple chemokines including the monocyte chemoattractants CCL2, CCL7, and CCL22. Importantly, blockade of G-protein coupled receptor-dependent signaling, and thereby chemokine receptor activity, inhibited IL-33-driven monocyte recruitment. CCR2 deficiency prevented recruitment of monocytes to the lung extravascular space during allergic sensitization, and resulted in reduced eosinophilia after allergen challenge. Thus, IL-33 plays a critical role in the initiation of type 2 inflammatory responses by inducing upregulation of chemokines that promote monocyte recruitment to the lung interstitium.