Transcriptional Control of Lung Macrophage Development

University Of California, San Diego, La Jolla CA

Investigators

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Abstract

? DESCRIPTION (provided by applicant): Newborn infants are highly susceptible to lung infection and inflammation. In preterm infants, infection prevents normal lung development and leads to bronchopulmonary dysplasia. Term newborns are also at risk, with bacterial pneumonia a leading cause of neonatal morbidity and mortality both in the U.S. and worldwide. In older children and adults, a specialized innate immune system protects the lung from pathogens and injury related to infection. While innate immunity in the newborn lung is clearly diminished, we do not yet clearly understand the molecular and cellular mechanisms putting these populations at risk. Identifying these key mechanisms will allow development of new therapies for preventing and treating neonatal disease. In the lung, macrophages are the key immune cell responsible for ingesting and removing particles, killing pathogens, recruiting additional immune cells, and promoting healing following injury. However, the role of macrophages in newborn lung innate immunity has been uncharacterized. Our previous work demonstrated using innovative mouse models that macrophages populate the fetal lung from the earliest stages of lung formation. These fetal lung macrophages are capable of responding to microbial substances well before they would be expected to have contact with the external environment. We also showed that macrophage activation was required and sufficient for causing inflammation in the fetal lung. In addition, fetal lung macrophage activation was the key initial step in inflammation-mediated arrest in lung development. Subsequent work in our lab showed macrophage derived IL-1ß plays a key role in inhibiting normal epithelial-mesenchymal integrations during lung morphogenesis. However, multiple expression and function of multiple components of the macrophage immune response appear to be developmentally regulated, with increased expression in more mature lungs. We therefore hypothesize that developmental maturation of lung macrophages determines how the inflammatory response causes lung disease. To test our hypothesis, we propose complementary approaches to better understand the molecular mechanisms regulating normal lung macrophage maturation and differentiation. We will also test how exposure of developing macrophages to activating stimuli not only generates an inflammatory response but also alters the normal transcriptional program controlling macrophage differentiation and maturation. Because early activation appears to accelerate cell maturation, we will test how premature maturation affects macrophage cell biology. These experiments will identify key basic mechanisms regulating how the lung innate immune system develops in both normal and disease settings. Our findings will therefore lay the foundation for future translational and therapeutic discovery and applications to improve pediatric health.