Dendritic cell immunoreceptor drives atopic dermatitis by modulating oxidized CaMKII-involved mast cell activation.

Xiaoyan Luo,Nathan K Archer,Yuko Kawakami,Yingchun Shen,Huan Yang,Toshiaki Kawakami,Peisong Gao,Jingsi Chen,Xinyue Hu,Wei Tu,Martin P Alphonse,Xiaoying Zhou,Mei Wan,Hua Wang

doi:10.1172/jci.insight.152559

Abstract

Allergens have been identified as potential triggers in patients with atopic dermatitis (AD). Patients with AD are highly sensitive to cockroach allergen. The underlying mechanism, however, remains undetermined. Here, we established a cockroach allergen–induced AD-like mouse model, and we demonstrate that repeated exposure to cockroach allergen led to aggravated mouse skin inflammation, characterized by increased type 2 immunity, type 2 innate lymphoid cells (ILC2s), and mast cells. Increased mast cells were also observed in patients with AD. Mast cell–deficient mice (KitW-sh/W-sh) showed diminished skin inflammation, suggesting that mast cells are required in allergen-induced skin inflammation. Furthermore, DC immunoreceptor (DCIR) is upregulated in skin mast cells of patients with AD and mediates allergen binding and uptake. DCIR–/– mice or reconstituted KitW-sh/W-sh mice with DCIR–/– mast cells showed a significant reduction in AD-like inflammation. Both in vitro and in vivo analyses demonstrate that DCIR–/– mast cells had reduced IgE-mediated mast cell activation and passive cutaneous anaphylaxis. Mechanistically, DCIR regulates allergen-induced IgE-mediated mast cell ROS generation and oxidation of calmodulin kinase II (ox-CaMKII). ROS-resistant CaMKII (MM-VVδ) prevents allergen-induced mast cell activation and inflammatory mediator release. Our study reveals a DCIR/ROS/CaMKII axis that controls allergen-induced mast cell activation and AD-like inflammation.

Highlights

Atopic dermatitis (AD) is a common chronic relapsing inflammatory skin disease that affects 15%–30% of children and approximately 5% of adults in industrialized countries, causing a significant negative impact on the quality of life of patients [1]
We first examined whether repetitive topical exposure to cockroach allergen can induce AD-like skin inflammation in a cockroach allergen– induced mouse model of AD modified from previous reports (Figure 1A) [43–45]
The dermatitis was further supported by Eczema Area and Severity Index (EASI) score, a method for quantifying the severity of clinical signs [46, 47], on day 2 after every patch removal (Figure 1C)

Summary

Introduction

Atopic dermatitis (AD) is a common chronic relapsing inflammatory skin disease that affects 15%–30% of children and approximately 5% of adults in industrialized countries, causing a significant negative impact on the quality of life of patients [1]. The etiology of AD is not fully understood, there is growing evidence supporting the role of specific allergens in perpetuating skin inflammation in sensitized patients with AD through impaired skin barrier and inappropriate immune responses to antigens [3, 4]. Food and inhalant allergens have been identified as potential trigger factors in sensitized patients with AD [5–7]. Cockroach allergen has been recognized as an important allergen associated with allergic diseases [8]. Most patients with AD are highly sensitive to cockroach allergen [9–12]. Little is known about how cockroach allergen triggers AD and its underlying mechanisms

Methods

Results

Conclusion