Lung CD103<sup>+</sup>dendritic cells and Clec9a signaling are required for neonatal hyperoxia-induced inflammatory responses to rhinovirus infection

Cui, Tracy X.; Fulton, Christina T.; Brady, A.; Zhang, Yingjian; Goldsmith, Adam M.; Popova, Antonia P.

doi:10.1152/ajplung.00334.2019

Cited by 5 publications

(15 citation statements)

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“…We have previously shown that hyperoxic exposure of neonatal mice (a model of BPD) increases the number of activated lung IL-12-producing, Clec9a+CD103+ DCs, induces lung pro-inflammatory responses and airway hyperreactivity following RV infection ( 31 ). We have also shown that CD103+ DCs and Clec9a signaling are required for hyperoxia-induced inflammatory responses to RV ( 32 ). In addition, we have found that hyperoxia induces airway cell death and increases F-actin levels in BALF supernatant ( 32 ).…”

Section: Resultsmentioning

confidence: 95%

“…Two days after the exposure completed, mice were inoculated with RV intranasally. We have previously published extensive data on sham controls for normoxia- and hyperoxia-exposed neonatal mice ( 32 ). Our goal for this study was to compare the effects of gelsolin on normoxia- and hyperoxia-exposed, RV infected mice, therefore we chose not to include a sham control for this study.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that hyperoxic exposure of neonatal mice increases F-actin levels in BALF supernatant ( 32 ). To assess the capacity of the actin-scavenger system in the airways, we evaluated the effect of hyperoxia on the balance of F-actin and gelsolin protein levels in the BALF supernatant.…”

Section: Resultsmentioning

confidence: 99%

“…We have also shown that CD103+ DCs and Clec9a signaling are required for hyperoxia-induced inflammatory responses to RV (32). In addition, we have found that hyperoxia induces airway cell death and increases F-actin levels in BALF supernatant (32). 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.…”

Section: In a Mouse Model Of Bpd Gelsolin Blocks Neonatal Hyperoxia-induced Inflammatory Responses To Rv Infectionmentioning

confidence: 99%

“…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 also 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.…”

Section: Introductionmentioning

confidence: 99%

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Gelsolin Attenuates Neonatal Hyperoxia-Induced Inflammatory Responses to Rhinovirus Infection and Preserves Alveolarization

et al. 2022

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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.

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Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: In a Mouse Model Of Bpd Gelsolin Blocks Neonatal Hyperoxia-induced Inflammatory Responses To Rv Infectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gelsolin Attenuates Neonatal Hyperoxia-Induced Inflammatory Responses to Rhinovirus Infection and Preserves Alveolarization

et al. 2022

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Lower peripheral blood CD4⁺ lymphocyte ratio is associated with severe bronchopulmonary dysplasia

Huang,

Xing,

Kong

2024

Pediatric Pulmonology

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ObjectiveTo elucidate the characteristics of lymphocyte subsets in bronchopulmonary dysplasia (BPD) diagnosis following Jensen's criterion to understand the spectrum of lymphocytes in different degrees of BPD.Study DesignThis single‐center retrospective cohort study included 120 neonates admitted to the neonatal intensive care unit between 1 July 2014 and 30 June 2021, who had undergone peripheral blood lymphocyte subpopulation detection.ResultsThirty‐one neonates were included in the control group, whereas 33 infants with BPD were included in the case group. In addition, we selected 56 infants with a gestational age (GA) <37 weeks without BPD who were receiving oxygen therapy. Among the three groups, the B cell and NK cell frequencies were significantly higher and the frequencies of T cells and CD4+ cells were significantly lower in the BPD group. In newborns without BPD, the distribution of T lymphocyte subsets was similar at different GAs. Comparing different degrees of BPD, the patients in the grades 2–3 BPD group had significantly lower percentages of T lymphocytes and CD4+ T cells than those in the other groups. Remarkably, the frequencies of NK cells were significantly higher in patients with grades 2–3 BPD, and the Treg cells slightly increased with BPD severity, although the differences were not significant.ConclusionHealthy neonates had similar ratios of lymphocyte subsets among different GAs; although as the GAs increased, the percentage of lymphocytes increased slightly. Severe BPD was associated with lower CD4+ T cells and higher NK cells. However, whether such changes were the cause or the consequence of BPD has not been determined.

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Vitamin D Ameliorates Apoptosis and Inflammation by Targeting the Mitochondrial and MEK1/2-ERK1/2 Pathways in Hyperoxia-Induced Bronchopulmonary Dysplasia

Hu¹,

Wu²,

Wang³

et al. 2022

JIR

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Bronchopulmonary dysplasia (BPD) is a common and severe complication in preterm infants. Vitamin D (VitD) has been reported to protect against BPD; however, its role in the mitochondria-mediated and MEK1/2-ERK1/2 pathways has not yet been reported. Methods: We first performed in vivo studies using neonatal C57BL/6 mice in which we induced BPD by exposing them to a hyperoxic environment (85% O 2 ). The mice were divided into room air (RA; 21% O 2 ), RA+VitD, BPD, and BPD+VitD groups. Hematoxylin and eosin and Masson's trichrome staining were used to evaluate lung injury. Inflammation and apoptosis were measured using ELISA, RT-qPCR, and TUNEL assays. We then analyzed BEAS-2B cells divided into the same groups along with an additional BPD+VitD+inhibitor group. Mitochondrial apoptosis was evaluated by transmission electron microscopy, mitochondrial membrane potential, and Western blotting. We then used VDR-shRNA to silence the Vitamin D Receptor (VDR) in the BEAS-2B cells. The inflammation, apoptotic rate, and the phosphorylated forms of MEK1/2 and ERK1/2 in cells were detected by RT-qPCR, flow cytometry, and Western blotting. Results: The mean linear intercept, septal thickness, and abnormal fibrosis increased, while radial alveolar count decreased in BPD lungs compared to RA lungs. VitD administration was able to ameliorate the phenotype in BPD lungs. IL-6, IFN-γ, and TNF-α expression and the apoptotic rate decreased in the BPD+VitD lung group. VitD pretreatment restored abnormal mitochondrial morphology, reduced mitochondrial membrane loss, and reduced the expression of cleaved caspase-3, Bax, and Bcl-2 in BEAS-2B cells. VitD administration also reduced IL-6, IFN-γ, and TNF-α mRNA, as well as pMEK1/2 and pERK1/2 expression and apoptosis rate in cells exposed to hyperoxia. Conclusion:We concluded that VitD treatment ameliorated apoptosis and inflammation by targeting the mitochondrial pathway and via the MEK1/2-ERK1/2 signaling pathway in BPD, thus supporting its potential therapeutic use in this condition.

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Lung CD103⁺dendritic cells and Clec9a signaling are required for neonatal hyperoxia-induced inflammatory responses to rhinovirus infection

Cited by 5 publications

References 58 publications

Gelsolin Attenuates Neonatal Hyperoxia-Induced Inflammatory Responses to Rhinovirus Infection and Preserves Alveolarization

Gelsolin Attenuates Neonatal Hyperoxia-Induced Inflammatory Responses to Rhinovirus Infection and Preserves Alveolarization

Lower peripheral blood CD4⁺ lymphocyte ratio is associated with severe bronchopulmonary dysplasia

Vitamin D Ameliorates Apoptosis and Inflammation by Targeting the Mitochondrial and MEK1/2-ERK1/2 Pathways in Hyperoxia-Induced Bronchopulmonary Dysplasia

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Lung CD103+dendritic cells and Clec9a signaling are required for neonatal hyperoxia-induced inflammatory responses to rhinovirus infection

Cited by 5 publications

References 58 publications

Gelsolin Attenuates Neonatal Hyperoxia-Induced Inflammatory Responses to Rhinovirus Infection and Preserves Alveolarization

Gelsolin Attenuates Neonatal Hyperoxia-Induced Inflammatory Responses to Rhinovirus Infection and Preserves Alveolarization

Lower peripheral blood CD4+ lymphocyte ratio is associated with severe bronchopulmonary dysplasia

Vitamin D Ameliorates Apoptosis and Inflammation by Targeting the Mitochondrial and MEK1/2-ERK1/2 Pathways in Hyperoxia-Induced Bronchopulmonary Dysplasia

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Lung CD103⁺dendritic cells and Clec9a signaling are required for neonatal hyperoxia-induced inflammatory responses to rhinovirus infection

Lower peripheral blood CD4⁺ lymphocyte ratio is associated with severe bronchopulmonary dysplasia