Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13–induced tissue responses and apoptosis

Abstract

Mouse breast regression protein 39 (BRP-39; Chi3l1) and its human homologue YKL-40 are chitinase-like proteins that lack chitinase activity. Although YKL-40 is expressed in exaggerated quantities and correlates with disease activity in asthma and many other disorders, the biological properties of BRP-39/YKL-40 have only been rudimentarily defined. We describe the generation and characterization of BRP-39−/− mice, YKL-40 transgenic mice, and mice that lack BRP-39 and produce YKL-40 only in their pulmonary epithelium. Studies of these mice demonstrated that BRP-39−/− animals have markedly diminished antigen-induced Th2 responses and that epithelial YKL-40 rescues the Th2 responses in these animals. The ability of interleukin13 to induce tissue inflammation and fibrosis was also markedly diminished in the absence of BRP-39. Mechanistic investigations demonstrated that BRP-39 and YKL-40 play an essential role in antigen sensitization and immunoglobulin E induction, stimulate dendritic cell accumulation and activation, and induce alternative macrophage activation. These proteins also inhibit inflammatory cell apoptosis/cell death while inhibiting Fas expression, activating protein kinase B/AKT, and inducing Faim 3. These studies establish novel regulatory roles for BRP-39/YKL-40 in the initiation and effector phases of Th2 inflammation and remodeling and suggest that these proteins are therapeutic targets in Th2- and macrophage-mediated disorders.

YKL-40/CHI3L1 drives inflammation on the road of tumor progression

“…Furthermore, this interleukin has been shown to regulate the production of chitinase-like proteins [36]. In OVA-sensitized and challenged mice, YKL-40/CHI3L1 expression was induced in airways presenting a significant degree of inflammation [37], which was greatly ameliorated in YKL-40/CHI3L1 KO mice.…”

“…Ma et al [32] demonstrated that a known decoy receptor of IL-13, IL-13Ra2, functions as a receptor for YKL-40/ CHI3L1. In comparing cell death of immune cells in wild-type with YKL-40/CHI3L1 KO mice, Lee et al [37] showed increased cell death in CD4 + T cells, macrophages, and eosinophils in the KO mice, indicating that YKL-40/CHI3L1 is anti-apoptotic. In assessing the pathways that YKL-40/CHI3L1 uses to regulate inflammatory cell apoptosis, enhanced levels of total and activated PKB/AKT were shown in wild-type compared with YKL-40/ CHI3L1 KO mice.…”

AMCase is a crucial regulator of type 2 immune responses to inhaled house dust mites

“…YKL-40-overexpressing transgenic mouse (17). However, the roles in immune responses of many other CLPs are still largely unknown.…”

“…Breast regression protein 39 (BRP-39) and its human homolog YKL-40 are CLPs induced in the aeroallergen asthma mouse model and human asthma patients, respectively (7,17). In KO mice in which BRP-39 was deleted, type 2 immune responses were diminished in the OVAinduced mouse model or IL-13-overexpressing transgenic mice, but the immune responses were rescued by crossing with an…”

Human YKL-39 is a pseudo-chitinase with retained chitooligosaccharide-binding properties

“…YKL-40 is also used as a disease marker in Type 1 Gaucher's disease and in solid-state tumour progression (reviewed in [26]). Knockout studies of the mouse orthologue of YKL-40 [BRP-39 (breast regression protein 39)] revealed a significant reduction in the Th2 inflammatory response and an increase in cellular apoptosis under challenge with ovalbumin, which was rescued by supplementing the BRP-39 protein [27]. There is a paucity of information about the biological function of YKL-39; nevertheless, the protein has been suggested as a diagnostic marker for the diagnosis and management of osteoarthritis based on increased expression levels in osteoarthritic cartilage [28,29].…”