PROJECT SUMMARY/ABSTRACT
A severe asthma endotype involving neutrophils infiltrating the airways with a Th17 dominant
milieu, and excessive airway remodeling and resistance to conventional therapies, has emerged
in patients in the past years. In a transcriptomic screen, we found that the TNF Superfamily
member LIGHT, was highly enriched in a murine model of severe asthma mimicking the human
disease, in addition to being enriched in the sputum of patients. This proposal will evaluate the
contribution of LIGHT signaling in 1) neutrophils to promote airway neutrophilia, 2) stromal cells
to promote pathological remodeling and steroid resistance, and 3) it will evaluate the pathogenic
role of Th17 cells as drivers of airway remodeling compared to Th2 cells, through LIGHT
production. Furthermore, we have evidence that the TNF Superfamily LIGHT decreases airway
remodeling and will address how LIGHT blockade compares to neutrophilic depletion, or IL17
neutralization, in decreasing NA symptoms: airway resistance, epithelial damage, fibroblasts
activation, and neutrophil recruitment. Lastly, this project will address whether the combinatorial
blockade of LIGHT and steroid treatment, can abrogate airway remodeling in severe asthma, in
the mouse model and the human lung-in-a-dish model we established.