Abstract
Surfactant protein A (SP-A) is well-known for its protective role in pulmonary immunity. Previous studies from our group have shown that SP-A mediates eosinophil activities, including degranulation and apoptosis. In order to identify potential binding partners on eosinophils for SP-A, eosinophil lysates were subjected to SP-A pull-down and tandem mass spectrometry (MS/MS) analysis. We identified one membrane-bound protein, myeloid-associated differentiation marker (MYADM), as a candidate SP-A binding partner. Blocking MYADM on mouse and human eosinophils ex vivo prevented SP-A from inducing apoptosis; blocking MYADM in vivo led to increased persistence of eosinophilia and airway hyper-responsiveness in an ovalbumin (OVA) allergy model and increased airways resistance and mucus production in a house dust mite (HDM) asthma model. Examination of a subset of participants in the Severe Asthma Research Program (SARP) cohort revealed a significant association between epithelial expression of MYADM in asthma patients and parameters of airway inflammation, including: peripheral blood eosinophilia, exhaled nitric oxide (FeNO) and the number of exacerbations in the past 12 months. Taken together, our studies provide the first evidence of MYADM as a novel SP-A-associated protein that is necessary for SP-A to induce eosinophil apoptosis and we bring to light the potential importance of this previously unrecognized transmembrane protein in patients with asthma.
Highlights
Surfactant protein A (SP-A) is well-known for its protective role in pulmonary immunity
We show a functional role for myeloid-associated differentiation marker (MYADM) in: (1) SP-A-mediated eosinophil apoptosis of murine and human eosinophils in vitro and (2) resolution of eosinophilia and airway hyperresponsiveness after allergen challenge in vivo
Our studies show that MYADM is a novel association partner for SP-A on eosinophils that is necessary for SP-A to induce eosinophil apoptosis and we bring to light the potential importance of this previously unrecognized transmembrane receptor in patients with asthma
Summary
Surfactant protein A (SP-A) is well-known for its protective role in pulmonary immunity. The success of corticosteroid therapies and anti-eosinophil biologics, Scientific Reports | (2021) 11:23392 Both of which contribute to the reduction of eosinophilia, albeit by different mechanisms, highlight the role eosinophils play in the pathology of asthma. We have determined that SP-A contributes to the resolution of eosinophilia by promoting eosinophil migration out of the lung tissue, and more remarkably, promoting eosinophil apoptosis in the lung lumen[20]. In addition to these phenotypes associated with resolution of eosinophilia, our group has shown that SP-A inhibits eosinophil peroxidase release, a toxic product that can compromise the integrity of the airway epithelia[16]. A genetic variation in the carbohydrate recognition domain of SP-A2 occurring at position 223, which results in a glutamine (Q) to a lysine (K) substitution, alters regulatory functions of SP-A in apoptosis and degranulation of e osinophils[11,20]
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