Chitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2
Chuan Hua He,
Chun Geun Lee,
Charles S. Dela Cruz,
Chang-Min Lee,
Yang Zhou,
Farida Ahangari,
Bing Ma,
Erica L. Herzog,
Stephen A. Rosenberg,
Yue Li,
Adel M. Nour,
Chirag R. Parikh,
Insa Schmidt,
Yorgo Modis,
Lloyd Cantley,
Jack A. Elias
Affiliations
Chuan Hua He
Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8057, USA
Chun Geun Lee
Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8057, USA
Charles S. Dela Cruz
Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8057, USA
Chang-Min Lee
Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8057, USA
Yang Zhou
Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8057, USA
Farida Ahangari
Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8057, USA
Bing Ma
Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8057, USA
Erica L. Herzog
Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8057, USA
Stephen A. Rosenberg
Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8057, USA
Yue Li
Molecular Biophysics and Biochemistry Department, Yale University, 266 Whitney Avenue, P.O. Box 208114, New Haven, CT 06520-8114, USA
Adel M. Nour
Molecular Biophysics and Biochemistry Department, Yale University, 266 Whitney Avenue, P.O. Box 208114, New Haven, CT 06520-8114, USA
Chirag R. Parikh
Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8057, USA
Insa Schmidt
Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8057, USA
Yorgo Modis
Molecular Biophysics and Biochemistry Department, Yale University, 266 Whitney Avenue, P.O. Box 208114, New Haven, CT 06520-8114, USA
Lloyd Cantley
Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8057, USA
Jack A. Elias
Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520-8057, USA
Members of the 18 glycosyl hydrolase (GH 18) gene family have been conserved over species and time and are dysregulated in inflammatory, infectious, remodeling, and neoplastic disorders. This is particularly striking for the prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1), which plays a critical role in antipathogen responses where it augments bacterial killing while stimulating disease tolerance by controlling cell death, inflammation, and remodeling. However, receptors that mediate the effects of GH 18 moieties have not been defined. Here, we demonstrate that Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2) and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex. We also demonstrate that Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms. Thus, IL-13Rα2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses.
