Inflammation in the developing preterm lung leads to disrupted airway morphogenesis and chronic lung disease in human neonates. However the molecular mechanisms linking inflammation and the pathways controlling airway morphogenesis remain unclear. Here we show that IL-1β released by activated fetal lung macrophages is the key inflammatory mediator that disrupts airway morphogenesis. In mouse lung explants, blocking IL-1β expression, post-translational processing, and signaling each protected the formation of new airways from the inhibitory effects of E. coli LPS. Consistent with a critical role of IL-1β, mice expressing a gain of function Nlrp3 allele and subsequent overactive inflammasome activity displayed abnormal saccular stage lung morphogenesis and died soon after birth. While the early stage fetal lung appeared capable of mounting an NF-κB mediated immune response, airway formation became more sensitive to inflammation later in development. This period of susceptibility coincided with higher expression of multiple inflammasome components, which could therefore increase the capability to release bioactive IL-1β. Macrophages from Nlrp3 gain of function mice also expressed higher levels of more mature cell surface markers, additionally linking inflammasome activation with macrophage maturation. These data identify developmental expression of the inflammasome and IL-1β release by fetal lung macrophages as key mechanisms and potential therapeutic targets for neonatal lung disease.

Lung macrophages mature after birth, placing newborn infants, particularly those born preterm, within a unique window of susceptibility to disease. We hypothesized that in preterm infants, lung macrophage immaturity contributes to the development of bronchopulmonary dysplasia (BPD), the most common serious complication of prematurity. By measuring changes in lung macrophage gene expression in preterm patients at risk of BPD, we show here that patients eventually developing BPD had higher inflammatory mediator expression even on the first day of life. Surprisingly, the ex vivo response to LPS was similar across all samples. Our analysis did however uncover macrophage signature genes whose expression increased in the first week of life specifically in patients resilient to disease. We propose that these changes describe the dynamics of human lung macrophage differentiation. Our study therefore provides new mechanistic insight into both neonatal lung disease and human developmental immunology.

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