Nicole G Hansbro, Chantal Donovan, W Scott Argraves, Qi Ge, Tatt Jhong Haw, Alexandra C Brown, Chris L Grainge, Alan C Hsu, Janette K Burgess, Gang Liu, Prema M Nair, Philip M Hansbro, Marion A Cooley, Jay C Horvat, Hock Tay, Jane E Bourke, Darryl A Knight, Paul S Foster, Andrew G Jarnicki, Brian G Oliver, Peter A Wark
Asthma is a chronic inflammatory disease of the airways. It is characterised by allergic airway inflammation, remodelling and hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin-1 (Fbln1) is an important ECM protein that stabilises collagen and other ECM proteins. Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that Fbln1c protein was increased in the lungs of mice with house duct mite (HDM)-induced chronic allergic airway disease (AAD). Genetic deletion and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c deficient (–/–) mice had reduced mucin MUC5AC, but not MUC5B protein levels in the airways compared to wild-type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c–/– mice with AAD also had reduced α-smooth muscle actin positive cells around the airways and reduced airway contractility compared to WT mice. These mice also had less airway inflammatory cells, as well as reduced levels of IL-5, IL-13, IL-33, TNF and CXCL1 levels in the lungs, and IL-5, IL-33, and TNF protein in lung-draining lymph nodes after HDM challenge. Therapeutic targeting of Fbln1c reduced the numbers of GATA3+ Th2 cells in lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL-5 and IL-13 protein from co-cultured dendritic cells and T cells re-stimulated with HDM. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium-treated controls Our data show that Fbln1c may be a therapeutic target in chronic asthma.
