Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity

Background

Expression of the urokinase plasminogen activator receptor (uPAR) is elevated in the airway epithelium in asthma; however, the contribution of uPAR to asthma pathogenesis and scope for therapeutic targeting remains unknown.

Objectives

To determine (i) the expression profile of uPAR in cultured human bronchial epithelial cells (HBEC) from asthma patients, (ii) the relationship between uPAR and the epithelial barrier, including blocking uPAR functions and (iii) the function of different uPAR isoforms.

Methods

uPAR levels in HBECs isolated from asthma patients and cells at air liquid interface (ALI) during differentiation were quantified. Transepithelial electrical resistance or electrical cell impedance sensing was used to relate uPAR levels to barrier properties, including effects of uPAR blocking antibodies. The functional effects of gain of function was determined using transcriptomics, in cells over-expressing membrane (muPAR), soluble cleaved (scuPAR) or soluble spliced (ssuPAR) isoforms.

Results

Elevated expression of uPAR was a feature of cultured HBECs from asthma patients, suggesting intrinsic alterations in asthma patient cells. Soluble uPAR levels inversely correlated with barrier properties of the HBEC layer in 2D and ALI. Blocking uPAR-integrin interactions enhanced barrier formation. The gain of function cells showed limited transcriptomic changes.

Conclusion

This study provides a significant advance in our understanding of the relationship between asthma, uPAR and the epithelial barrier, where elevated circulating uPAR results in a reduced cell barrier, a phenotype prevalent in asthma.