Budesonide reduces the bronchial epithelial response to a viral mimic in T2high asthma, and boosts anti-microbial responses in T2low asthma

Abstract

<b>Introduction:</b>&nbsp;Inhaled corticosteroids (ICS) reduce exacerbations in asthma. However, the different mechanisms underlying the effect of these drugs in T2-high and T2-low phenotypes are largely unknown. <b>Aim:</b>&nbsp;To evaluate the effect of ICS treatment on bronchial epithelial response to TLR3 stimulation in T2-high and T2-low asthma patients. <b>Methods:</b>&nbsp;Bronchial epithelial cells (BECs) from patients with T2-high (FeNO&gt;25ppb; N=8) and T2-low (N=9) asthma, before and after inhaled budesonide (6 weeks; 1600mg/day), were used. Poly(I:C) (TLR3 agonist) was used as viral mimic. Proteomic (LC-MS/MS) and RTqPCR analyses were performed in BECs homogenates, and ELISA in BECs supernatants. <b>Results:</b>&nbsp;171 proteins were upregulated in poly(I:C)-stimulated BECs from T2-high/atopic vs. T2-low/non-atopic patients (p&lt;0.05/FC&gt;1.5), including proteins from biological process categories related to immune system (e.g., GO:0045087, GO:0016032, or GO:0034097). ICS treatment reduced this exaggerated BECs response in T2-high patients (4 proteins up, 220 down; p&lt;0.05/FC&gt;1.5), whereas the opposite effect was found in T2-low asthma (34 up; 7 down; p&lt;0.05/FC&gt;1.5). Moreover, an increased IFN-β release in response to poly (I:C) was found in BECs from T2-low patients after ICS treatment (p&lt;0.05), and the same was shown for TNF-α both at gene (p=0.05) and protein (p&lt;0.05) level. <b>Conclusion:</b> Budesonide treatment had differing but beneficial effects on the airway epithelial response to a viral mimic in both T2-high and T2 low asthma.