Fibrinogen and lipopolysaccharide promote TLR4-dependent glucocorticoid resistance in airway mycosis-driven allergic airway disease.

Glucocorticoid-refractory asthma is a severe disease type linked to both T helper type 2 (T2) high and T2 low, neutrophil-high asthma endotypes, but the mechanisms governing glucocorticoid resistance are largely unknown. We show that glucocorticoid-resistant mouse allergic airway disease is linked to airway mycosis and lung-specific production of fibrinogen cleavage products (cryptokines). Mice challenged with the allergenic fungus Aspergillus niger and low-dose inhaled lipopolysaccharide (LPS) showed exaggerated airway hyperresponsiveness (AHR), developed T2 high and neutrophilic airway inflammation recapitulating severe asthma. AHR was not attenuated by glucocorticoid therapy, but required expression of Toll-like receptor 4 (TLR4). Low-dose intranasal LPS alone induced AHR in a manner previously shown for Aspergillus proteinase-derived cryptokines that required TLR4. We show further that cryptokines significantly enhance fibrinogen production in both the mouse lung and from primary human airway epithelial cells and that cryptokine-induced AHR is glucocorticoid resistant. Thus, glucocorticoid resistance in asthma may in part result from airway-specific production of the TLR4 ligands cryptokines and LPS. These findings suggest novel approaches to the management of glucocorticoid-resistant asthma.