Role of Chitinase 3-like-1 in IL-18-induced pulmonary Type- 1, -2 and -17 inflammation, alveolar destruction and airway fibrosis in the murine lung

ABSTRACT Chitinase 3-like 1 (Chi3l1), which is also called YKL-40 in man and BRP-39 in mice, is the prototypic chitinase like protein (CLP). Recent studies have highlighted its impressive ability to regulate the nature of tissue inflammation, and the magnitude of tissue injury and fibroproliferative repair. This can be nicely appreciated in studies which highlight its induction after cigarette smoke exposure where it inhibits alveolar destruction and the genesis of pulmonary emphysema. IL-18 is also known to be induced and activated by cigarette smoke and, in murine models, the IL-18 pathway has been shown to be necessary and sufficient to generate COPD-like inflammation, fibrosis and tissue destruction. However, the relationship between Chi3l1 and IL-18 has not been defined. To address this issue we characterized the expression of Chi3l1/BRP-39 in control and lung-targeted IL-18 transgenic mice. We also characterized the effects of transgenic IL-18 in mice with wild type and null Chi3l1 loci. The former studies demonstrated that IL-18 is a potent stimulator of Chi3l1/BRP-39 and that this stimulation is mediated via IFN-γ-, IL-13- and IL-17A-dependent mechanisms. They latter demonstrated that, in the absence of Chi3l1/BRP-39, IL-18 induced Type 2 and Type 17 inflammation and fibrotic airway remodeling were significantly ameliorated while Type 1 inflammation, emphysematous alveolar destruction and the expression of cytotoxic T lymphocyte (CTL) perforin, granzyme and Raet1 expression were enhanced. These studies demonstrate that IL-18 is a potent stimulator of Chi3l1 and that Chi3l1 is an important mediator of IL-18 induced inflammatory, fibrotic, alveolar remodeling and cytotoxic responses. (Words Count : 249, limit : 250) Key Words: Chi3l1, IL-18, airway fibrosis, alveolar remodeling, Th1, Th2, Th17,