The innate immune response in fetal lung mesenchymal cells targets VEGFR2 expression and activity.

Medal RM, Im AM, Yamamoto Y, Lakhdari O, Blackwell TS, Hoffman HM, Sahoo D, Prince LS
Am J Physiol Lung Cell Mol Physiol. 2017 312 (6): L861-L872

PMID: 28336813 · PMCID: PMC5495951 · DOI:10.1152/ajplung.00554.2016

In preterm infants, soluble inflammatory mediators target lung mesenchymal cells, disrupting airway and alveolar morphogenesis. However, how mesenchymal cells respond directly to microbial stimuli remains poorly characterized. Our objective was to measure the genome-wide innate immune response in fetal lung mesenchymal cells exposed to the bacterial endotoxin lipopolysaccharide (LPS). With the use of Affymetrix MoGene 1.0st arrays, we showed that LPS induced expression of unique innate immune transcripts heavily weighted toward CC and CXC family chemokines. The transcriptional response was different between cells from E11, E15, and E18 mouse lungs. In all cells tested, LPS inhibited expression of a small core group of genes including the VEGF receptor Although best characterized in vascular endothelial populations, we demonstrated here that fetal mouse lung mesenchymal cells express and respond to VEGF-A stimulation. In mesenchymal cells, VEGF-A increased cell migration, activated the ERK/AKT pathway, and promoted FOXO3A nuclear exclusion. With the use of an experimental coculture model of epithelial-mesenchymal interactions, we also showed that VEGFR2 inhibition prevented formation of three-dimensional structures. Both LPS and tyrosine kinase inhibition reduced three-dimensional structure formation. Our data suggest a novel mechanism for inflammation-mediated defects in lung development involving reduced VEGF signaling in lung mesenchyme.

Copyright © 2017 the American Physiological Society.

MeSH Terms (13)

Animals Cell Communication Cell Movement Epithelial Cells Fetus Gene Expression Regulation, Developmental Immunity, Innate Lipopolysaccharides Lung Mesoderm Mice, Inbred C57BL Signal Transduction Vascular Endothelial Growth Factor Receptor-2

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