Chitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2

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 alpha 2 (IL-13R alpha 2) and that Chi3l1, IL-13R alpha 2, 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/beta-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-beta 1 production via IL-13R alpha 2-dependent mechanisms. Thus, IL-13R alpha 2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses.