NF-κB Signaling in Fetal Lung Macrophages Disrupts Airway Morphogenesis

Abstract

Bronchopulmonary dysplasia is a common pulmonary complication of extreme prematurity. Arrested lung development leads to bronchopulmonary dysplasia, but the molecular pathways that cause this arrest are unclear. Lung injury and inflammation increase disease risk, but the cellular site of the inflammatory response and the potential role of localized inflammatory signaling in inhibiting lung morphogenesis are not known. Here we show that tissue macrophages present in the fetal mouse lung mediate the inflammatory response to lipopolysaccharide and that macrophage activation inhibits airway morphogenesis. Macrophage depletion or targeted inactivation of the NF-κB signaling pathway protected airway branching in cultured lung explants from the effects of lipopolysaccharide. Macrophages also appear to be the primary cellular site of IL-1β production following lipopolysaccharide exposure. Conversely, targeted NF-κB activation in transgenic macrophages was sufficient to inhibit airway morphogenesis. Macrophage activation in vivo inhibited expression of multiple genes critical for normal lung development, leading to thickened lung interstitium, reduced airway branching, and perinatal death. We propose that fetal lung macrophage activation contributes to bronchopulmonary dysplasia by generating a localized inflammatory response that disrupts developmental signals critical for lung formation.

Macrophages and CSF-1

“…110 In the lung, macrophages are evident as early as E10 in the mouse located within the mesenchyme and surrounding the forming lung buds and elongating bronchi. 111,112 We have previously observed that during branching morphogenesis, macrophages are located abundantly within developing branch points (Fig. 3).…”

“…Indeed, the inflammatory activation of macrophages during development not only contributes to tissue damage and disruption of organ development through pro-inflammatory injury, but may also skew macrophages away from their trophic functions. 111,139,140 Inflammatory activation of fetal lung macrophages through NF-κB signaling was found to upregulate proinflammatory mediators such as IL-1β and alter expression of Wnt7b, bone morphogenic protein (BMP)4 111 and fibroblast growth factor (FGF)-10. 139 And while inflammatory challenges such as lipopolysaccharide (LPS) or IL-1β administration in models of chorioamnionitis promote accelerated maturation, the mechanism is distinct from alveolarisation, characterized by a lung pathology associated with BPD.…”

Interactions between NF-κB and SP3 Connect Inflammatory Signaling with Reduced FGF-10 Expression

“…Inhibition of FGF-10 does not involve direct interaction between NF-B and canonical DNA binding elements in the Fgf-10 promoter (24). We hypothesized that NF-B might therefore inhibit FGF-10 expression by regulating the activity of other transcription factors.…”

Intraductal Injection of LPS as a Mouse Model of Mastitis: Signaling Visualized via an NF-κB Reporter Transgenic

“…Finally, the NGL transgenic reporter mice used here and the similarly functioning HLL reporter mice 17 have been used in numerous studies to verify, quantify, and track the up or down regulation of NF-κB activity within a variety of disease and developmental models including acute lung injury, lung cancer, airway branching morphogenesis, insulin resistance, obesity, and myocardial infarction 1,[17][18][19][20][21] . This model provides an additional example of the utility of these reporter transgenics.…”