title: 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.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Chuan Hua
authors.initials: CH
authors.lastname: He
authors.forename: Erica L
authors.initials: EL
authors.lastname: Herzog
authors.forename: Xueyan
authors.initials: X
authors.lastname: Peng
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Lee
authors.forename: Tung H
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Mridu
authors.initials: M
authors.lastname: Gulati
authors.forename: Bernadette R
authors.initials: BR
authors.lastname: Gochuico
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Martin L
authors.initials: ML
authors.lastname: Slade
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
mesh_terms: D054392:Adipokines / Q000097:blood* / Q000235:genetics; D000328:Adult; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D000071451:Chitinase-3-Like Protein 1; D004195:Disease Models, Animal; D005260:Female; D006023:Glycoproteins / Q000097:blood* / Q000235:genetics; D022861:Hermanski-Pudlak Syndrome / Q000097:blood* / Q000150:complications / Q000235:genetics / Q000473:pathology; D006801:Humans; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000235:genetics / Q000378:metabolism; D037102:Lectins / Q000097:blood* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000097:blood* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology
chemical_list: D054392:Adipokines; D015415:Biomarkers; C084533:CHI3L1 protein, human; C509289:Chil1 protein, mouse; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D053663:Interleukin-13 Receptor alpha2 Subunit; D037102:Lectins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor