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

Abstract

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.

Pathogenic implication of epidermal scratch injury in psoriasis and atopic dermatitis

“…133 CHI3L1/YKL-40 promotes fibrotic process 133 and further accelerates Th2 deviation. 134 These results suggest a possibility that the scratch-induced IL-13Ra2 upregulation may convert the keratinocyte response from IL-13-dominant to CHI3L1/YKL-40-dominant pattern.…”

Oxidative Stress and Atopic Dermatitis

“…In particular, macrophages have been observed to accumulate in large amounts in the acutely and chronically inflamed skin of patients with atopic dermatitis, playing a key role in the pathogenesis of this disease. They exert proinflammatory functions like antigen-presenting phagocytosis and the production of inflammatory cytokines and growth factors, so contributing to the characteristic chronic inflammation of atopic dermatitis [13]. In a murine model of AD, the chitinase 3-like 1 protein was shown to affect Th2 inflammation, M2 macrophage activation, and skin barrier function [14].…”

Chitinase 3-Like 1 Contributes to Food Allergy via M2 Macrophage Polarization

“…Macrophages are known to affect Th2 inflammation, and our previous study demonstrated that CHI3L1 is predominantly induced in macrophages during Th2-dependent skin inflammation. 19 We therefore used flow cytometric analysis to determine whether CHI3L1 is expressed in intestinal macrophages during food allergy. Strikingly, the population of CHI3L1-positive cells in intestinal macrophages was higher in the OVA-treated WT mice than in the control mice ( Fig.…”

“…Recent studies have also indicated that CHI3L1 is involved in M2 macrophage polarization in atopic dermatitis and RSV infection. 19 43 This effect could be due to Th2 cytokines, such as IL-4 and IL-13, which are M2 polarization drivers. 45 Therefore, we suspect that increased expression of Th2 cytokines is involved in the development of the M2 phenotype, and that these synergistic effects may promote food allergy.…”

“…14 15 16 Previous studies have also demonstrated that serum levels of CHI3L1 were significantly elevated in patients with asthma or atopic dermatitis, suggesting that CHI3L1 is associated with allergic disease. 17 18 19 CHI3L1 is reportedly expressed in epithelial cells and macrophages at the sites of Th2 inflammation and contributes to M2 macrophage differentiation by activating local dendritic cells. 20 CHI3L1 also contributes to tissue remodeling and apoptosis as well as Th2 inflammation.…”