Neonatal hyperoxia promotes asthma-like features through IL-33–dependent ILC2 responses

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d313433e253">BACKGROUND</h5> <p id="P1">Premature infants often require oxygen supplementation and, therefore, are exposed to oxidative stress. Following oxygen exposure, preterm infants frequently develop chronic lung disease and have a significantly increased risk of asthma. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d313433e258">OBJECTIVE</h5> <p id="P2">We sought to identify the underlying mechanisms by which neonatal hyperoxia promotes asthma development. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d313433e263">METHODS</h5> <p id="P3">Mice were exposed to neonatal hyperoxia followed by a period room air recovery. A group of mice were also intranasally exposed to house dust mite antigen (HDM). Assessments were performed at various time points for evaluation of airway hyperresponsiveness (AHR), eosinophilia, mucus production, inflammatory gene expression, T helper (Th) and group 2 innate lymphoid cell (ILC2) responses. Sera from term- and preterm-born infants were also collected and the levels of IL-33 and type 2 cytokines were measured. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d313433e268">RESULTS</h5> <p id="P4">Neonatal hyperoxia induced asthma-like features including AHR, mucus hyperplasia, airway eosinophilia, and type 2 pulmonary inflammation. In addition, neonatal hyperoxia promoted allergic Th responses to HDM exposure. Elevated IL-33 levels and ILC2 responses were observed in the lungs most likely due to oxidative stress caused by neonatal hyperoxia. IL-33 receptor signaling and ILC2s were vital for the induction of asthma-like features following neonatal hyperoxia. Serum IL-33 levels correlated significantly with serum levels of IL-5 and IL-13, but not IL-4 in preterm infants. </p> </div><div class="section"> <a class="named-anchor" id="S5"> <!-- named anchor --> </a> <h5 class="section-title" id="d313433e273">CONCLUSION</h5> <p id="P5">These data demonstrate that an axis involving IL-33 and ILC2s is important for the development of asthma-like features following neonatal hyperoxia and suggest therapeutic potential for targeting IL-33, ILC2s, and oxidative stress to prevent and/or treat asthma development related to prematurity. </p> </div>