Role of pulmonary epithelial arginase‐II in activation of fibroblasts and lung inflammaging

Elevated arginases including type‐I (Arg‐I) and type‐II isoenzyme (Arg‐II) are reported to play a role in aging, age‐associated organ inflammaging, and fibrosis. A role of arginase in pulmonary aging and underlying mechanisms are not explored. Our present study shows increased Arg‐II levels in aging lung of female mice, which is detected in bronchial ciliated epithelium, club cells, alveolar type 2 (AT2) pneumocytes, and fibroblasts (but not vascular endothelial and smooth muscle cells). Similar cellular localization of Arg‐II is also observed in human lung biopsies. The age‐associated increase in lung fibrosis and inflammatory cytokines, including IL‐1β and TGF‐β1 that are highly expressed in bronchial epithelium, AT2 cells, and fibroblasts, are ameliorated in arg‐ii deficient (arg‐ii ( −/− )) mice. The effects of arg‐ii ( −/−) on lung inflammaging are weaker in male as compared to female animals. Conditioned medium (CM) from human Arg‐II‐positive bronchial and alveolar epithelial cells, but not that from arg‐ii ( −/− ) cells, activates fibroblasts to produce various cytokines including TGF‐β1 and collagen, which is abolished by IL‐1β receptor antagonist or TGF‐β type I receptor blocker. Conversely, TGF‐β1 or IL‐1β also increases Arg‐II expression. In the mouse models, we confirmed the age‐associated increase in IL‐1β and TGF‐β1 in epithelial cells and activation of fibroblasts, which is inhibited in arg‐ii ( −/−) mice. Taken together, our study demonstrates a critical role of epithelial Arg‐II in activation of pulmonary fibroblasts via paracrine release of IL‐1β and TGF‐β1, contributing to pulmonary inflammaging and fibrosis. The results provide a novel mechanistic insight in the role of Arg‐II in pulmonary aging.