Mucin 1 deficiency mediates corticosteroid insensitivity in asthma.
Por:
Milara, Javier, Morell, Anselm, de Diego, Alfredo, Artigues, Enrique, Morcillo, Esteban, Cortijo, Julio
Publicada:
1 ene 2019
Resumen:
BACKGROUND: The loss of corticosteroid efficacy is an important issue in
severe asthma management and may lead to poor asthma control and
deterioration of airflow. Recent data indicate that Mucin 1 (MUC1)
membrane mucin can mediate corticosteroid efficacy in chronic
rhinosinusitis, but the role of MUC1 in uncontrolled severe asthma is
unknown. The objective was to analyze the previously unexplored role of
MUC1 on corticosteroid efficacy in asthma.
METHODS: Mucin 1 expression was evaluated by real-time PCR in human
bronchial epithelial cells (HBEC) and blood neutrophils from
uncontrolled severe asthma (n=27), controlled mild asthma (n=16), and
healthy subjects (n=13). IL-8, MMP9, and GM-CSF were measured by ELISA
in HBEC and neutrophils. An asthma model of ovalbumin (OVA) was used in
MUC1 KO and WT C57BL/6 mice according to ARRIVE guidelines.
RESULTS: Mucin 1-CT expression was downregulated in bronchial epithelial
cells and peripheral blood neutrophils from severe asthma patients
compared with mild asthma and healthy subjects (P<0.05). Daily dose of
inhaled corticosteroids (ICS) inversely correlated with MUC1 expression
in neutrophils from mild and severe asthma (rho=-0.71; P<0.0001).
Dexamethasone showed lower anti-inflammatory effects in severe asthma
peripheral blood neutrophils and HBECs stimulated with
lipopolysaccharide (LPS) than in cells from mild asthma. Glucocorticoid
receptor (GR)-alpha phosphorylated at serine 226 was increased in cells
from severe asthma, and the MUC1-CT/GRalpha complex was downregulated in
severe asthma cells. OVA asthma model in MUC1 KO mice was resistant to
the anti-inflammatory effects of dexamethasone.
CONCLUSION: Mucin 1-CT modulates corticosteroid efficacy invitro and
invivo asthma models.
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