Allergen-induced airway matrix remodeling in mice can be prevented or reversed by targeting chitinase-like proteins

Abstract

Chitinase-like proteins (CLPs) are established biomarkers of inflammation and airway remodeling in asthma, yet their direct contribution toward disease pathogenesis is unknown. In a mouse model of type 2/type 17 airway inflammation induced by house dust mite, ragweed, and Aspergillus fumigatus (DRA) allergens, we demonstrate that murine CLPs Ym1 (Chil3) and Ym2 (Chil4) exert distinct and potent effects on airway extracellular matrix (ECM) composition during chronic lung pathology. Using both Ym1-knockout (Chil3^−/−) and Ym2-knockdown (Chil4^KD/KD) mice, we found that these CLPs have fundamental roles in airway remodeling that are independent of interleukin-13 (IL-13) and IL-17A signaling pathways. Antibody-mediated inhibition of CLPs after pathology has developed reverses airway remodeling independently of chronic inflammation. However, this inhibition is not sufficient to reduce airway hyperresponsiveness (AHR) in allergic animals. Instead, the absence of CLPs increases epithelial damage and leads to a loss of bronchial epithelial integrity. This work disentangles chronic IL-13 and IL-17A signaling from the development of allergic airway pathology and reveals CLPs as orchestrators of airway remodeling that can produce both protective and adverse outcomes.