Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 64, Issue 6, Pages 698-708Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2020-0007OC
Keywords
asthma; IL-17A; SR-BI receptor; neutrophilia; adrenal insufficiency
Funding
- Brody School of Medicine internal seed bridge grant
- National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES102005, ZIA-ES102025-09]
- National Institutes of Health Center for Human Health and the Environment grant [P30ES025128]
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Asthma is a common respiratory disease characterized by airway inflammation, hyperreactivity, and remodeling, driven by various T-helper cell types. Scavenger receptor SR-BI has been found to play a role in regulating inflammation in allergic asthma, primarily by maintaining adrenal function to attenuate pulmonary neutrophilic inflammation and IL-17A production.
Asthma is a common respiratory disease currently affecting more than 300 million worldwide and is characterized by airway inflammation, hyperreactivity, and remodeling. It is a heterogeneous disease consisting of corticosteroid-sensitive T-helper cell type 2-driven eosinophilic and corticosteroid-resistant, T-helper cell type 17-driven neutrophilic phenotypes. One pathway recently described to regulate asthma pathogenesis is cholesterol trafficking. Scavenger receptors, in particular SR-BI (scavenger receptor class B type I), are known to direct cellular cholesterol uptake and efflux. We recently defined SR-BI functions in pulmonary host defense; however, the function of SR-BI in asthma pathogenesis is unknown. To elucidate the role of SR-BI in allergic asthma, SR-BI-sufficient (SR-BI+/+) and SR-BI-deficient (SR-BI-/-) mice were sensitized (Days 0 and 7) and then challenged (Days 14, 15, and 16) with a house dust mite (HDM) preparation administered through oropharyngeal aspiration. Airway inflammation and cytokine production were quantified on Day 17. Whencompared with SR-BI+/+ mice, the HDM-challenged SR-BI-/- mice had increased neutrophils and pulmonary IL-17A production in BAL fluid. This augmented IL-17A production in SR-BI-/- mice originated from a non-T-cell source that included neutrophils and alveolar macrophages. Given that SR-BI regulates adrenal steroid hormone production, we tested whether the changes in SR-BI-/- mice were glucocorticoid dependent. Indeed, SR-BI-/- mice were adrenally insufficient during the HDM challenge, and corticosterone replacement decreased pulmonary neutrophilia and IL-17A production in SR-BI-/- mice. Taken together, these data indicate that SR-BI dampens pulmonary neutrophilic inflammation and IL-17Aproduction in allergic asthma at least in part by maintaining adrenal function.
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