Role of Chitinase 3–Like-1 in Interleukin-18–Induced Pulmonary Type 1, Type 2, and Type 17 Inflammation; Alveolar Destruction; and Airway Fibrosis in the Murine Lung

Abstract

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.

The Blood Transcriptome of Experimental Melioidosis Reflects Disease Severity and Shows Considerable Similarity with the Human Disease

“…S2). Consistent with the histological evidence of fibrosis in chronically infected spleens (11), we observed upregulation of numerous genes associated in other systems with fibrosis and tissue remodelling (18) (19), although these genes were invariably expressed to a greater extent in tissue than blood (Fig. 4H).…”

Chitinase 3‐like 1 drives allergic skin inflammation via Th2 immunity and M2 macrophage activation

“…Consistent with this finding, a recent study demonstrated that BRP‐39 −/− CD4 + T cells are prone to Th1 differentiation, and that they show reduced Th2 differentiation via an IFNγ signalling pathway . Additionally, in the absence of CHI3L1, IL‐18‐induced pulmonary inflammatory responses were significantly ameliorated by downregulation of Th2 and Th17 responses …”

Tissue dual RNA-seq allows fast discovery of infection-specific functions and riboregulators shaping host–pathogen transcriptomes

“…2B and Dataset S3). The pattern of up-regulated inflammatory cytokines/chemokine receptors and strong enrichment of neutrophil-specific transcripts (e.g., stefin A/cystatin A, prokineticin 2, Schlafen 4, Fpr1, and Clec4e) involved in neutrophil mobilization, neutrophil-mediated phagocytosis, and neutrophil extracellular traps formation (24)(25)(26) highlight that the host immune response is dominated by infiltrating neutrophils (Dataset S3). This finding is consistent with previous observations that the number of neutrophils within murine Peyer's patches increases ∼100-fold (14).…”