Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease
Yang Zhou, … , Chun Geun Lee, Jack A. Elias
Yang Zhou, … , Chun Geun Lee, Jack A. Elias
Published June 29, 2015
Citation Information: J Clin Invest. 2015;125(8):3178-3192. https://doi.org/10.1172/JCI79792.
View: Text | PDF
Research Article Pulmonology

Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease

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 patients with subtypes HPS-1 and HPS-4, which both result from defects in biogenesis of lysosome-related organelle complex 3 (BLOC-3). The prototypic chitinase-like protein chitinase 3–like–1 (CHI3L1) plays a protective role in the lung by ameliorating cell death and stimulating fibroproliferative repair. Here, we demonstrated that circulating CHI3L1 levels are higher in HPS patients with pulmonary fibrosis compared with those who remain fibrosis free, and that these levels associate with disease severity. Using murine HPS models, we also determined that these animals have a defect in the ability of CHI3L1 to inhibit epithelial apoptosis but exhibit exaggerated CHI3L1-driven fibroproliferation, which together promote HPS fibrosis. These divergent responses resulted from differences in the trafficking and effector functions of two CHI3L1 receptors. Specifically, the enhanced sensitivity to apoptosis was due to abnormal localization of IL-13Rα2 as a consequence of dysfunctional BLOC-3–dependent membrane trafficking. In contrast, the fibrosis was due to interactions between CHI3L1 and the receptor CRTH2, which trafficked normally in BLOC-3 mutant HPS. These data demonstrate that CHI3L1-dependent pathways exacerbate pulmonary fibrosis and suggest CHI3L1 as a potential biomarker for pulmonary fibrosis progression and severity in HPS.

Authors

Yang Zhou, Chuan Hua He, Erica L. Herzog, Xueyan Peng, Chang-Min Lee, Tung H. Nguyen, Mridu Gulati, Bernadette R. Gochuico, William A. Gahl, Martin L. Slade, Chun Geun Lee, Jack A. Elias

×

Figure 7

CHI3L1 binds to and promotes fibrosis development through CRTH2.

Options: View larger image (or click on image) Download as PowerPoint
CHI3L1 binds to and promotes fibrosis development through CRTH2. (A) CHI...
(A) CHI3L1 and CRTH2 Co-IP. Immunoprecipitation (IP) of CHI3L1 or CRTH2 was undertaken, and the precipitate was then evaluated by Western immunoblot (IB) analysis as noted. Lung lysates from WT [Il13 Tg (–)] and Il13 Tg (+) mice were employed. (B) Colocalization of CHI3L1 and CRTH2. THP-1 cells were incubated in the presence or absence of anti-CHI3L1–biotin antibody or anti-CRTH2 IgG antibody without permeabilization. The cells were then washed and stained with streptavidin-PE (SA-PE) and anti-IgG–APC and subjected to flow cytometric analysis. Each experiment was undertaken at least three times.(C–E) WT, pale ear, and CHI3L1 Tg mice were subjected to intratracheal bleomycin administration. Mice were treated with CRTH2 inhibitor or its vehicle control. (C and D) Total lung collagen was quantified using Sircol assay on day 14. (E) mRNA levels of Cd206 were evaluated by qRT-PCR. The noted values are the mean ± SEM of evaluations of 6 mice in each group. (F and G) Mouse peritoneal macrophages were transfected with control or CRTH2 siRNA and treated with recombinant CHI3L1 (500 ng/ml) for 24 hours. mRNA levels of (F) Cd206 and (G) arginase-1 were evaluated by qRT-PCR. The noted values are the mean ± SEM of 3 independent experiments. Comparisons between groups were conducted by 2-way ANOVA with Bonferroni’s post hoc test. *P ≤ 0.05, **P ≤ 0.01.