Research Paper Chitinase-3-like Protein 1: A Progranulin Downstream Molecule and Potential Biomarker for Gaucher Disease Jinlong Jian a , Yuehong Chen a , Rossella Liberti a , Wenyu Fu a , Wenhuo Hu a , Rachel Saunders-Pullman b , Gregory M. Pastores c,1 , Ying Chen d , Ying Sun e , Gregory A. Grabowski e , Chuan-ju Liu a,f, ⁎ a Department of Orthopaedic Surgery, New York University Medical Center, New York, NY, 10003, USA b Department of Neurology, Mount Sinai Beth Israel Medical Center, New York, NY 10003, USA c Department of Neurology, New York University School of Medicine, 550 First Ave, New York, NY 10016, USA d Depression Evaluation Service, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA e The Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA f Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA abstract article info Article history: Received 2 January 2018 Received in revised form 20 January 2018 Accepted 20 January 2018 Available online 31 January 2018 We recently reported that progranulin (PGRN) is a novel regulator of glucocerebrosidase and its deficiency associates with Gaucher Diseases (GD) (Jian et al., 2016a; Jian et al., 2018). To isolate the relevant downstream molecules, we performed a whole genome microarray and mass spectrometry analysis, which led to the isolation of Chitinase-3-like-1 (CHI3L1) as one of the up-regulated genes in PGRN null mice. Elevated levels of CHI3L1 were confirmed by immunoblotting and immunohistochemistry. In contrast, treatment with recombinant Pcgin, a derivative of PGRN, as well as imigluerase, significantly reduced the expressions of CHI3L1 in both PGRN null GD model and the fibroblasts from GD patients. Serum levels of CHIT1, a clinical biomarker for GD, were significantly higher in GD patients than healthy controls (51.16 ± 2.824 ng/ml vs 35.07 ± 2.099 ng/ml, p b 0.001). Similar to CHIT1, serum CHI3L1 was also significantly increased in GD patients compared with healthy controls (1736 ± 152.1 pg/ml vs 684.7 ± 68.20 pg/ml, p b 0.001). Whereas the PGRN level is significantly reduced in GD patients as compared to the healthy control (91.56 ± 3.986 ng/ml vs 150.6 ± 4.501, p b 0.001). Collectively, these results indicate that CHI3L1 may be a previously unrecognized biomarker for diagnosing GD and for evaluating the therapeutic effects of new GD drug(s). © 2018 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords: Progranulin Gaucher disease Chitinase-3-like-1 Lysosomal storage diseases 1. Introduction Gaucher disease (GD), common lysosomal storage disease (LSD), is caused by mutations in GBA1 with resultant defective glucocerebrosidase (GCase) activity and consequent accumulation of its substrate β-glucosylceramide (β-GlcCer) in macrophages and other cell types (Jian et al., 2016a). There are three types of GD based on its primary central nervous system (CNS) involvement: Type 1 does not manifest with early onset primary CNS disease and has previously been described as non-neuropathic. Patients with GD types 2 and 3 have primary CNS impairments. Type 2 features acute neuropathic disease of infancy. Type 3 is marked by chronic neuropathy with highly variable primary CNS onset and involvement. The peripheral manifestations of GD include hepatosplenomegaly and pancytopenia, due to bone marrow infiltration and splenic sequestration. Although GBA1 mutations are the primary cause of GD, there is broad heterogene- ity in clinical manifestations even among patients carrying the same GBA1 mutations, ranging from very early disease onset to very mild clinical presentations (Biegstraaten et al., 2011; Elstein et al., 2010). These diverse variations are not directly attributable to different GBA1 mutations and may relate to unidentified modifier genes. PGRN is also known as granulin–epithelin precursor (GEP) (Zanocco-Marani et al., 1999), proepithelin (PEPI) (Shoyab et al., 1990; Plowman et al., 1992), acrogranin (Anakwe and Gerton, 1990), and GP88/PC-cell derived growth factor (PCDGF) (Zhou et al., 1993). PGRN is a growth factor with multiple functions, including promoting cell proliferation, stimulating wound healing (Zhao and Bateman, 2015; He et al., 2003) and regulating immune response (Fu et al., 2016; Jian et al., 2013a; Jian et al., 2018; Liu et al., 2014; Liu and Bosch, 2012; Mundra et al., 2016; Wei et al., 2014a; Wei et al., 2016; Williams et al., 2016). PGRN is also an anti-inflammatory molecule that directly binds to TNFR, inhibits TNFα/TNFR1 inflammatory signal- ing (Liu and Bosch, 2012; Jian et al., 2013b; Liu, 2011; Tian et al., 2014; EBioMedicine 28 (2018) 251–260 ⁎ Corresponding author at: Rm 1608, Department of Orthopedic Surgery, New York University Medical Center, 301 East 17th Street, New York, NY 10003, USA. E-mail address: chuanju.liu@med.nyu.edu (C. Liu). 1 Current address: National Centre for Inherited Metabolic Disorders. Department of Medicine, Mater Misericordiae University Hospital and University College Dublin, Ireland. https://doi.org/10.1016/j.ebiom.2018.01.022 2352-3964/© 2018 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents lists available at ScienceDirect EBioMedicine journal homepage: www.ebiomedicine.com