Depletion of Lung Macrophages Increases Steroid Sensitivity in a Mouse Model of Severe Allergic Airway Inflammation
Year: 2021
Type: conference-abstract
Abstract: Introduction: Severe pediatric asthma is characterized by airway hyperresponsiveness (AHR), restricted airflow, airway remodeling, and decreased sensitivity to corticosteroids.Although the adaptive immune system has been studied in the context of severe asthma, the role of lung macrophages and their impact on corticosteroid sensitivity remains poorly understood.In the present study, we tested the hypothesis that depletion of lung macrophages would increase corticosteroid sensitivity in a mouse model of severe allergic airway inflammation.Methods: Newborn mice were sensitized with PBS or ovalbumin (OVA) with an aluminum hydroxide (alum) adjuvant via intraperitoneal injection (IP) once a week for three weeks.To deplete lung macrophages, mice were intratracheally administered empty or clodronate loaded liposomes 24 hours before allergen challenge.Mice were intranasally challenged with PBS or c-di-GMP + OVA 3 consecutive days between 6-7 weeks of life and IP injected with vehicle or 1 mg/kg fluticasone propionate (FP).The following day, bronchoalveolar lavage (BAL) was collected while lung function, total and differential BAL cell counts, flow cytometry, cytokine, and histopathological analyses were also performed.Results: c-di-GMP + OVA-challenged mice exhibited increased BAL macrophage morphological activation and increased TNFα levels that were not reduced with 1 mg/kg FP.To deplete lung macrophages, we administered clodronate loaded liposomes.Mice administered empty liposomes and challenged with c-di-GMP + OVA exhibited increased AHR, BAL immune cells, and airway inflammation that was not reduced by 1 mg/kg FP. c-di-GMP + OVA-challenged mice who received clodronate and 1 mg/kg FP exhibited significantly reduced AHR and airway inflammation.Although clodronate liposomes did not reduce total BAL immune cells, lung macrophages were reduced, confirming depletion by clodronate.Histological analyses and scoring show that c-di-GMP + OVA-challenged mice who received clodronate and 1 mg/kg FP had lower immune cell aggregation in peribronchiolar spaces.Conclusions: Depletion of lung macrophages increased steroid sensitivity by reducing AHR and airway inflammation in the presence of corticosteroids.Our novel data suggest that lung macrophages promote corticosteroid insensitivity during severe allergic airway inflammation and may be a cellular target to alleviate severe pediatric asthma.These studies are funded by NIH R00 HL131682-05 (Britt and Jackson).
Institution: Nationwide Children's Hospital
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4229483843