Abstract
Prematurity and bronchopulmonary dysplasia (BPD) increase the risk of asthma later in life. Supplemental oxygen therapy is a risk factor for chronic respiratory symptoms in infants with BPD. Hyperoxia induces cell injury and release of damage-associated molecular patterns (DAMPs). Cytoskeletal filamentous actin (F-actin) is a DAMP which binds Clec9a, a C-type lectin selectively expressed on CD103+ dendritic cells (DCs). Co-stimulation of Clec9a and TLR3 induces maximal proinflammatory responses. We have shown that neonatal hyperoxia (a model of BPD) increases lung IL-12+Clec9a+CD103+ DCs, pro-inflammatory responses and airway hyperreactivity following rhinovirus (RV) infection. CD103+ DCs and Clec9a are required for these responses. Hyperoxia increases F-actin levels in bronchoalveolar lavage fluid (BALF). We hypothesized that the F-actin severing protein gelsolin attenuates neonatal hyperoxia-induced Clec9a+CD103+ DC-dependent pro-inflammatory responses to RV and preserves alveolarization. We exposed neonatal mice to hyperoxia and treated them with gelsolin intranasally. Subsequently we inoculated the mice with RV intranasally. Alternatively, we inoculated normoxic neonatal mice with BALF from hyperoxia-exposed mice (hyperoxic BALF), RV and gelsolin. We analyzed lung gene expression two days after RV infection. For in vitro studies, lung CD11c+ cells were isolated from C57BL/6J or Clec9agfp-/- mice and incubated with hyperoxic BALF and RV. Cells were analyzed by flow cytometry. In neonatal mice, gelsolin blocked hyperoxia-induced Il12p40, TNF-α and IFN-γ mRNA and protein expression in response to RV infection. Similar effects were observed when gelsolin was co-administered with hyperoxic BALF and RV. Gelsolin decreased F-actin levels in hyperoxic BALF in vitro and inhibited hyperoxia-induced D103lo DC expansion and inflammation in vivo. Gelsolin also attenuated hyperoxia-induced hypoalveolarization. Further, incubation of lung CD11c+ cells from WT and Clec9agfp-/- mice with hyperoxic BALF and RV, showed Clec9a is required for maximal hyperoxic BALF and RV induced IL-12 expression in CD103+ DCs. Finally, in tracheal aspirates from mechanically ventilated human preterm infants the F-actin to gelsolin ratio positively correlates with FiO2, and gelsolin levels decrease during the first two weeks of mechanical ventilation. Collectively, our findings demonstrate a promising role for gelsolin, administered by inhalation into the airway to treat RV-induced exacerbations of BPD and prevent chronic lung disease.
Highlights
Prematurity and bronchopulmonary dysplasia (BPD), a chronic lung disease that affects preterm-born infants, are associated with chronic asthma-like symptoms, including recurrent wheezing and airflow obstruction lasting into adulthood [1,2,3,4]
We identified a primary role for filamentous actin (F-actin), present in hyperoxic bronchoalveolar lavage fluid (BALF) supernatant to promote inflammatory responses to RV infection in neonatal mice, and for gelsolin to block these responses
Since gelsolin depolymerizes F-actin decreasing its binding to Clec9a [47], we examined the effects of gelsolin on neonatal hyperoxia-induced inflammatory responses to RV infection
Summary
Prematurity and bronchopulmonary dysplasia (BPD), a chronic lung disease that affects preterm-born infants, are associated with chronic asthma-like symptoms, including recurrent wheezing and airflow obstruction lasting into adulthood [1,2,3,4]. Using a mouse model of BPD, we have shown that early-life hyperoxic exposure increases lung IL-12-producing Clec9a+CD103+ dendritic cells (DCs), pro-inflammatory responses and airway hyperreactivity following RV infection [31]. We have demonstrated that neonatal hyperoxia increases the dead cell number and F-actin levels in bronchoalveolar lavage fluid (BALF), and that CD103+ DCs and Clec9a are required for hyperoxia-induced inflammatory responses to RV [32]. These results implicate necrotic cell F-actin in hyperoxia-induced inflammatory responses to RV
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