Acidic Mammalian Chitinase Is Secreted via an ADAM17/Epidermal Growth Factor Receptor-dependent Pathway and Stimulates Chemokine Production by Pulmonary Epithelial Cells

Abstract

Acidic mammalian chitinase (AMCase) is expressed in an exaggerated fashion in epithelial cells at sites of pulmonary T helper cell type 2 inflammation and plays important roles in the pathogenesis of anti-parasite and asthma-like responses. However, the mechanisms that control epithelial cell AMCase secretion and its effector responses have not been adequately defined. To address these issues, we used in vivo and in vitro experimental systems to define the pathways of epithelial AMCase secretion and its epithelial regulatory effects. Here we demonstrate that, in murine T helper cell type 2 modeling systems, AMCase colocalizes with the epidermal growth factor receptor (EGFR) and ADAM17 (a membrane disintegrin and metallopeptidase 17) in lung epithelial cells. In vitro cotransfection experiments in A549 cells demonstrated that AMCase and EGFR physically interact with each other. Cotransfection of AMCase and EGFR also increased, whereas EGFR inhibition decreased AMCase secretion. Interestingly, AMCase secretion was not significantly altered by treatment with EGF but was significantly decreased when the upstream EGFR transactivator ADAM17 was inhibited. AMCase secretion was also decreased when the EGFR-downstream Ras was blocked. Transfected and recombinant AMCase induced epithelial cell production of CCL2, CCL17, and CXCL8. These studies demonstrate that lung epithelial cells secrete AMCase via an EGFR-dependent pathway that is activated by ADAM17 and mediates its effects via Ras. They also demonstrate that the AMCase that is secreted feeds back in an autocrine and/or paracrine fashion to stimulate pulmonary epithelial cell chemokine production.

Chitinase 3-Like 1 (Chil1) Regulates Survival and Macrophage-Mediated Interleukin-1β and Tumor Necrosis Factor Alpha during Pseudomonas aeruginosa Pneumonia

“…The 18-glycosyl hydrolase protein family is composed of true chitinases and chitinase-like proteins (20,21,50). True chitinases possess the ability to cleave their natural ligand, chitin, while chitinase-like proteins can bind to chitin but lack the ability to cleave chitin due to point mutations in the cleavage site (20,50).…”

Role of Breast Regression Protein–39 in the Pathogenesis of Cigarette Smoke–Induced Inflammation and Emphysema

“…Cells were then incubated for 30 minutes at 48C with specific antibodies for surface-marker staining for F4/80, CD45, Gr-1, and CD11b to identify macrophages or neutrophils. Lung epithelial cells were characterized according to a gating algorithm described previously (31). All antibodies and FACS reagents were from BD Biosciences.…”

Foxa2 Programs Th2 Cell-Mediated Innate Immunity in the Developing Lung

“…Th2-associated inflammatory mediators, including acidic chitinase (Chia), chitinase 3-like 1 (Chi3l1), chitinase 3-like 3 (Chi3l3), and chitinase 3-like 4 (Chi3l4) mRNAs, were increased in Foxa2 Δ/Δ mice. Chitinases and chitinase-like proteins are believed to play a key role in the innate immunity to parasites and other infectious agents and may play an important role in the pathogenesis of allergy and/or asthma and regulation of eosinophilia and eotaxin induction (48)(49)(50). Chia is induced via a Th2-specific, IL-13-mediated pathway in lung epithelial cells and macrophages and is increased in lungs of asthmatics (48).…”

“…Chia is induced via a Th2-specific, IL-13-mediated pathway in lung epithelial cells and macrophages and is increased in lungs of asthmatics (48). Chia stimulates chemokine production by pulmonary epithelial cells (50). Deletion of Foxa2 from lung epithelium disrupted Th1-Th2 balance, inducing a large number of Th2 cytokines and associated signaling pathways.…”