IL-1β and Inflammasome Activity Link Inflammation to Abnormal Fetal Airway Development.

Stouch AN, McCoy AM, Greer RM, Lakhdari O, Yull FE, Blackwell TS, Hoffman HM, Prince LS
J Immunol. 2016 196 (8): 3411-20

PMID: 26951798 · PMCID: PMC5315059 · DOI:10.4049/jimmunol.1500906

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.

Copyright © 2016 by The American Association of Immunologists, Inc.

MeSH Terms (16)

Animals Bronchopulmonary Dysplasia Carrier Proteins Disease Models, Animal Inflammasomes Inflammation Interleukin-1beta Lipopolysaccharides Lung Macrophages Mice Mice, Inbred C57BL Mice, Knockout NF-kappa B NLR Family, Pyrin Domain-Containing 3 Protein Signal Transduction

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