Chitinase 3-like 1 (Chi3l1), which is also called YKL-40 in humans and BRP-39 in mice, is the prototypic
chitinase-like
protein. 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 appreciated in studies that highlight its induction after cigarette
smoke exposure, during which 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
chronic obstructive pulmonary disease-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. The latter studies 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, whereas type 1
inflammation, emphysematous alveolar destruction, and the expression of cytotoxic T lymphocyte
perforin,
granzyme, and
retinoic acid early transcript 1 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.