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Early-life hyperoxia-induced Flt3L drives neonatal lung dendritic cell expansion and proinflammatory responses
Tracy X Cui1, Alexander E Brady1, Ying-Jian Zhang1
1Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, United States.
Insights
Early life exposure to high oxygen levels primes lung immune cells in mice, increasing inflammation risk in infants with bronchopulmonary dysplasia (BPD). This priming involves Flt3L, a growth factor that expands dendritic cells (DCs).
Area of Science:
- Immunology
- Neonatal Medicine
- Respiratory Medicine
Background:
- Infants born prematurely with bronchopulmonary dysplasia (BPD) experience chronic respiratory issues, particularly after viral infections.
- The underlying mechanisms for these persistent symptoms, especially concerning immune responses, remain unclear.
- Previous research linked hyperoxia-induced lung CD103+ dendritic cells (DCs) to exaggerated inflammation following rhinovirus (RV) infection in a BPD mouse model.
Purpose of the Study:
- To investigate the hypothesis that early-life hyperoxia promotes Flt3L expression, leading to the expansion and activation of lung CD103+ DCs.
- To determine if this Flt3L-mediated DC expansion contributes to inflammation in a mouse model of BPD.
- To explore the correlation between Flt3L, inflammatory markers, and BPD development in preterm infants.
Main Methods:
- Neonatal mice were exposed to hyperoxia to model BPD.
- Flow cytometry and transcriptional analysis were used to assess lung CD103+ and CD11bhi DCs.
- Flt3L expression was measured, and anti-Flt3L antibodies were used to block DC development and inflammatory responses.
- Tracheal aspirates from preterm infants were analyzed for FLT3L, IL-12, and IFN-γ levels.
Main Results:
- Hyperoxia increased the number and pro-inflammatory gene expression of lung CD103+ DCs and CD11bhi DCs in neonatal mice.
- Hyperoxia elevated Flt3L expression, and blocking Flt3L with antibodies inhibited CD103+ DC development and neutralized hyperoxia's effect on CD11bhi DCs.
- Anti-Flt3L treatment reduced hyperoxia-induced inflammation in response to RV infection.
- Preterm infants who developed BPD had higher levels of FLT3L, IL-12, and IFN-γ, with FLT3L positively correlating with pro-inflammatory cytokines.
Conclusions:
- Early-life hyperoxia primes lung dendritic cell development and function, mediated by Flt3L.
- Flt3L plays a critical role in hyperoxia-induced expansion and activation of lung DCs, contributing to inflammation.
- These findings highlight Flt3L as a potential therapeutic target for preventing BPD-associated chronic respiratory symptoms.
Abstract:
Premature infants with chronic lung disease, bronchopulmonary dysplasia (BPD), develop recurrent cough and wheezing following respiratory viral infections. The mechanisms driving the chronic respiratory symptoms are ill-defined. We have shown that hyperoxic exposure of neonatal mice (a model of BPD) increases the activated lung CD103+ dendritic cells (DCs) and these DCs are required for exaggerated proinflammatory responses to rhinovirus (RV) infection. Since CD103+ DC are essential for specific antiviral responses and their development depends on the growth factor Flt3L, we hypothesized that early-life hyperoxia stimulates Flt3L expression leading to expansion and activation of lung CD103+ DCs and this mediates inflammation. We found that hyperoxia numerically increased and induced proinflammatory transcriptional signatures in neonatal lung CD103+ DCs, as well as CD11bhi DCs. Hyperoxia also increased Flt3L expression. Anti-Flt3L antibody blocked CD103+ DC development in normoxic and hyperoxic conditions, and while it did not affect the baseline number of CD11bhi DCs, it neutralized the effect of hyperoxia on these cells. Anti-Flt3L also inhibited hyperoxia-induced proinflammatory responses to RV. In tracheal aspirates from preterm infants mechanically-ventilated for respiratory distress in the first week of life levels of FLT3L, IL-12p40, IL-12p70 and IFN-γ were higher in infants who went on to develop BPD and FLT3L levels positively correlated with proinflammatory cytokines levels. This work highlights the priming effect of early-life hyperoxia on lung DC development and function and the contribution of Flt3L in driving these effects.
