Yang Zhou
Brown University, USA
Title: Chitinase 3-like-1 and Its Receptors in Hermansky-Pudlak Syndrome-associated Lung Disease
Biography
Biography: Yang Zhou
Abstract
Hermansky-Pudlak Syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles. Pulmonary fibrosis is the major cause of morbidity and mortality in BLOC-3 mutant HPS-1 and HPS-4 patients. Chitinase 3-like-1 (CHI3L1), a prototypic chitinase-like protein, plays a protective role by ameliorating cell death and stimulating fibroproliferative repair. Here we demonstrate that circulating CHI3L1 levels are higher in HPS patients with pulmonary fibrosis compared to those that remain fibrosis-free, and that these levels associate with disease severity. Using murine models we also demonstrate that a defect in CHI3L1 inhibition of epithelial apoptosis and exaggerated CHI3L1-driven fibroproliferation play important roles in HPS fibrosis. Lastly we demonstrate that these divergent responses are mediated by differences in the trafficking and effector functions of two CHI3L1 receptors. Specifically, the enhanced sensitivity to apoptosis is due to the BLOC-3 dependent, and thus abnormal, trafficking of IL-13Ra2. In contrast, the fibrosis is due to interactions of CHI3L1 and CRTH2, which traffics normally in BLOC-3 HPS.