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.
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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

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Figure 1

CHI3L1 levels are increased in HPS patients.

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CHI3L1 levels are increased in HPS patients. (A) Plasma CHI3L1 is increa...
(A) Plasma CHI3L1 is increased in HPS-1 (n = 125) and HPS-4 (n = 4) patients compared with age-matched normal controls (n = 38) and HPS-3, HPS-5, and HPS-6 patients (n = 18). (B) Plasma CHI3L1 is increased in HPS-1 and HPS-4 patients with lung disease (n = 94) compared with patients without lung disease (n = 35). The samples represent the two subsets of the BLOC-3 HPS samples shown in A. (C) Plasma CHI3L1 is higher in patients with severe disease according to FVC (n = 61 [FVC ≥80%], n = 42 [FVC 60%–79%], and n = 26 [FVC ≤59%]). (D) Plasma CHI3L1 is higher in patients with severe disease according to DLCO (n = 51 [DLCO ≥80%], n = 39 [DLCO 60%–79%], and n = 34 [DLCO ≤59%]). (E) Plasma CHI3L1 levels correlate with FVC (n = 129). (F) Plasma CHI3L1 levels correlate with DLCO (n = 129). Nonparametric data were assessed using Mann-Whitney U analysis (A and B) or Spearman correlations (E and F). Normally distributed data were compared using ANOVA with Bonferroni’s post hoc test (C and D). *P ≤ 0.05, **P ≤ 0.05, ***P ≤ 0.001, ****P ≤ 0.0001.