Background: Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by defective skin barrier and Th2 immune responses. Chitinase 3‐like 1 (CHI3L1), also known as breast regression protein 39 (BRP‐39) in mice and human homologue YKL‐40, plays important roles in Th2 inflammation and allergen sensitization. CHI3L1 has been implicated in a variety of diseases including asthma characterized by inflammation, apoptosis and tissue remodelling, but its role in AD remains elusive.Objective: The aim of this study was to investigate the role of CHI3L1 in the development and progression of AD.Results: We investigated YKL‐40 levels in the serum and skin of AD patients by ELISA and immunofluorescence, respectively. Using a murine model of AD induced by ovalbumin (OVA), we investigated Th2 immune responses, M2 macrophage activation and skin barrier gene expression using wild‐type (WT) and BRP‐39 null mutant (BRP‐39^−/−) mice.YKL‐40 level was significantly increased in serum of AD patients. In addition, both mRNA and protein expression levels of BRP‐39 were higher in OVA‐sensitized WT mice than in control mice. OVA‐sensitized BRP‐39^−/− mice showed decreased epidermal thickness, lower total serum IgE, Th2 cytokine levels and CD4⁺ effector T cell populations than OVA‐sensitized WT mice. Induction of BRP‐39 was dominant in dermal macrophages. BRP‐39 deficiency was found to be involved in M2 macrophage activation. Consistently, the YKL‐40 level in the skin of AD patients was higher than in normal subjects and it was expressed in dermal macrophages. BRP‐39 deficiency attenuated dysregulation of skin barrier and tight junction genes.Conclusions and Clinical Relevance: These findings demonstrate that CHI3L1 mediates the development of AD induced by OVA, affecting Th2 inflammation, M2 macrophage activation and skin barrier function.

Kim EG, et al. Allergy Asthma Immunol Res. 2020 Nov;12(6):1012-1028. https://doi.org/10.4168/aair.2020.12.6.1012

Background: Chitotriosidase (chitinase 1, Chit1), a major true chitinase in humans, is induced in childhood asthma and has been implicated in the pathogenesis of a variety of inflammatory and tissue remodeling responses. However, the role and the mechanisms that underlie these contributions to the diseases have not been defined. We hypothesized that Chit1 plays a significant role in the pathogenesis of allergic asthma.Methods: Wild‐type and Chit1‐deficient mice and cells in culture were used to define the roles of Chit1 in models of allergic adaptive Th2 inflammation. In addition, the levels of sputum Chit1 were evaluated in pediatric asthma patients and compared to control.Results: The levels of sputum Chit1 were significantly increased in the patients with childhood asthma. Mice with Chit1 null mutation demonstrated enhanced allergic Th2 inflammatory and cytokine and IgE responses to OVA or house dust mite allergen sensitization and challenge. However, the expression levels of TGF‐β1 were significantly decreased with a diminished number of Foxp3⁺ regulatory T cells (Treg) in the lungs of Chit1^−/− mice compared to WT controls. In vitro, the absence of Chit1 significantly reduced TGF‐β‐stimulated conversion of CD4⁺CD25⁻ naïve T cells to CD4⁺Foxp3⁺ Treg cells, suggesting Chit1 is required for optimal effect of TGF‐β1 in Treg cell differentiation.Conclusion: Chit1 plays a protective role in the pathogenesis of allergic inflammation and asthmatic airway responses via regulation of TGF‐β expression and Foxp3⁺ Treg cells.

Mammalian chitinase released by airway epithelia is thought to be an important mediator of disease manifestation in an experimental model of asthma. However, the intracellular signaling mechanisms engaged by exogenous chitinase in human airway epithelial cells are unknown. Here, we investigated the direct effects of exogenous chitinase from Streptomyces griseus on Ca2+ signaling in human airway epithelial cells. Spectrofluorometry was used to measure intracellular Ca2+ concentration ([Ca2+]i) in fura-2-AM–loaded cells. S. griseus chitinase induced dose-dependent [Ca2+]i increases in normal human bronchial epithelial cells and promoted [Ca2+]i oscillations in H292 cells. Chitinase-induced [Ca2+]i oscillations were independent of extracellular Ca2+, suggesting that the observed [Ca2+]i increases were due to Ca2+ release from intracellular stores. Accordingly, after depleting endoplasmic reticulum (ER) Ca2+ with the ER Ca2+ ATPase inhibitor, thapsigargin, chitinase-mediated [Ca2+]i increases were abolished. Treatment with the phospholipase C (PLC) inhibitor U73122 or the 1, 4, 5-trisinositolphosphate (IP3) receptor inhibitor 2-APB attenuated chitinase-induced [Ca2+]i increases. Desensitization of protease-activated receptor-2 (PAR-2) by repetitive agonist stimulation or siRNA-mediated PAR-2 knock-down revealed that chitinase-mediated [Ca2+]i increases were exclusively mediated by PAR-2 activation. Finally, chitinase was found to cleave a model peptide representing the cleavage site of PAR-2 and enhanced IL-8 production. These results indicate that exogenous chitinase is a potent proteolytic activator of PAR-2 that can directly induce PLC/IP3-dependent Ca2+ signaling in human airway epithelial cells.