The innate immune response in fetal lung mesenchymal cells targets VEGFR2 expression and activity.
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 receptorVegfr2Although best characterized in vascular endothelial populations, we demonstrated here that fetal mouse lung mesenchymal cells expressVegfr2and 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.
Department of Pediatrics, University of California, San Diego, and Rady Children's Hospital, San Diego, California; and.
Rachel M
RM
Medal
Departments of Pediatrics, Medicine, Developmental and Cell Biology, and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Amanda M
AM
Im
Departments of Pediatrics, Medicine, Developmental and Cell Biology, and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Yasutoshi
Y
Yamamoto
Department of Pediatrics, University of California, San Diego, and Rady Children's Hospital, San Diego, California; and.
Omar
O
Lakhdari
Departments of Pediatrics, Medicine, Developmental and Cell Biology, and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Timothy S
TS
Blackwell
Department of Pediatrics, University of California, San Diego, and Rady Children's Hospital, San Diego, California; and.
Hal M
HM
Hoffman
Department of Pediatrics, University of California, San Diego, and Rady Children's Hospital, San Diego, California; and.
Debashis
D
Sahoo
Department of Pediatrics, University of California, San Diego, and Rady Children's Hospital, San Diego, California; and lprinceucsd@gmail.com.
Lawrence S
LS
Prince
D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005333:Fetus / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000196:embryology*; D008648:Mesoderm / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
D008070:Lipopolysaccharides; D040301:Vascular Endothelial Growth Factor Receptor-2
cell migration; chemokines; epithelial-mesenchymal interactions; innate immunity; lung development