323 - The Role of Neonatal Neutrophilic Cells (NNC) for Maturation of Airway Immunity and Lung Inflammation in Neonates

Publication Number: 323.6755

Jessica D.. Ruehle, Heidelberg University, Medical Faculty, Department of Neonatology, Heidelberg, Baden-Wurttemberg, Germany; Stefanie Dietz-Ziegler, Heidelberg University, Medical Faculty, Department of Neonatology, Heidelberg, Baden-Wurttemberg, Germany; Janine Hebel, Childrens University Hospital Tübingen, Tuebingen, Baden-Wurttemberg, Germany; christian F. Poets, Tübingen University Hospital, Tuebingen, Baden-Wurttemberg, Germany; Christian Gille, Heidelberg University, Heidelberg, Baden-Wurttemberg, Germany; Natascha Köstlin-Gille, University Hospital Tübingen, Tübingen, Baden-Wurttemberg, Germany

Background: Bronchopulmonary dysplasia (BPD) is one of the most important complications in extremely preterm infants. The etiology of BPD is multifactorial and inflammation seems to play an important role in its pathogenesis. Neutrophils are the first immune effector cells responding to inflammation. But, there are significant differences in the immune response of neutrophils between adults and neonates with functional deficits in the pro-inflammatory reaction and the presence of a suppressive subpopulation, the so called myeloid-derived suppressor cells (MDSC), in neonatal neutrophilic cells (NNC).

Objective: We aimed to investigate the properties of the lung NNC, their role in the maturation of the immune system and the development of the microbiome, and consequently in the pathogenesis of BPD.

Design/Methods: We quantified NNC in the lungs of neonatal mice at different timepoints and analyzed their suppressive activity on T cell proliferation by FACS. In depletion experiments, we analyzed pulmonary immune cell compositions and airway microbiome as well as BPD development in newborn mice after depletion of NNC by administration of an anti-Ly6G antibody to lactating dams. Lastly, we analyzed the effect of intranasal administration of in vitro generated MDSC on BPD development.

Results: Neonatal lungs contained high numbers of NNC, which decreased sharply over the first postnatal weeks. In functional assays, NNC isolated from the lungs of newborn mice immediately after birth had strong T cell suppressive activity compared to neutrophilic cells isolated from adult lungs and suppressive activity decreased during the first week of live. The strong accumulation of NNC in the lungs was detectable only immediately after birth and not already prenatally, suggesting a massive influx of NNC into the lungs at the time of birth. Depletion of NNC altered immune cell homeostasis and microbiome composition in the lungs of newborn mice and significantly improved lung histology after BPD induction. Interestingly, intranasal administration of MDSC had a strong protective effect on BPD development.

Conclusion(s): The functional properties of lung NNC seem to change rapidly after birth, showing a loss of suppressive activity. Depletion of NNC affects lung immune maturation and microbiome development. Both the depletion of NNC and the intranasal administration of MDSC protect newborn mice from developing BPD. Our results suggest that there is a shift in the functionality of NNC away from tolerogenic properties towards inflammatory activity due to environmental influences and that targeting NNC functions may be a strategy to prevent BPD.