title: IL-1β and Inflammasome Activity Link Inflammation to Abnormal Fetal Airway Development.
abstract: 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. In this article, 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, posttranslational processing, and signaling protected the formation of new airways from the inhibitory effects ofEscherichia coliLPS. Consistent with a critical role for IL-1β, mice expressing a gain-of-functionNlrp3allele and subsequent overactive inflammasome activity displayed abnormal saccular-stage lung morphogenesis and died soon after birth. Although 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 that could increase the ability to release bioactive IL-1β. Macrophages fromNlrp3gain-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.
authors.affiliation: Department of Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, La Jolla, CA 92093;
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Stouch
authors.affiliation: Department of Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, La Jolla, CA 92093;
authors.forename: Alyssa M
authors.initials: AM
authors.lastname: McCoy
authors.affiliation: Department of Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, La Jolla, CA 92093;
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Greer
authors.affiliation: Department of Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, La Jolla, CA 92093;
authors.forename: Omar
authors.initials: O
authors.lastname: Lakhdari
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232;
authors.forename: Fiona E
authors.identifier: http://orcid.org/0000-0003-1636-7942
authors.initials: FE
authors.lastname: Yull
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: Department of Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, La Jolla, CA 92093;
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.affiliation: Department of Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, La Jolla, CA 92093; lprinceucsd@gmail.com.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Prince
mesh_terms: D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000196:embryology; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D058847:Inflammasomes / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology*; D008070:Lipopolysaccharides; D008168:Lung / Q000196:embryology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015398:Signal Transduction / Q000276:immunology
chemical_list: D002352:Carrier Proteins; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse