Dendritic cell immunoreceptor drives atopic dermatitis by modulating oxidized CaMKII-involved mast cell activation
Xiaoyan Luo, Jingsi Chen, Huan Yang, Xinyue Hu, Martin P. Alphonse, Yingchun Shen, Yuko Kawakami, Xiaoying Zhou, Wei Tu, Toshiaki Kawakami, Mei Wan, Nathan K. Archer, Hua Wang, Peisong Gao
Xiaoyan Luo, Jingsi Chen, Huan Yang, Xinyue Hu, Martin P. Alphonse, Yingchun Shen, Yuko Kawakami, Xiaoying Zhou, Wei Tu, Toshiaki Kawakami, Mei Wan, Nathan K. Archer, Hua Wang, Peisong Gao
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Research Article Dermatology Immunology

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

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.

Authors

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

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Figure 7

DCIR regulates IgE-mediated mast cell activation and allergic responses.

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DCIR regulates IgE-mediated mast cell activation and allergic responses....
(A and B) BMMCs were confirmed and FcεRI expression was detected in BMMCs from WT and DCIR–/– mice by flow cytometry analysis. (C) Scheme of experimental protocol for IgE-mediated mast cell activation. (D) Flow cytometry analysis of CD107a expression in DNP-activated mast cells at different time points (n = 3). (E) ELISA analyses of β-hexosaminidase and histamine levels in supernatants of DNP-activated BMMCs from WT and DCIR–/– mice (n = 6). (F) Representative images of Evans blue–stained extravasation into ear skin of DNP-treated WT and DCIR–/– mice and quantification of the extravasation of Evans blue leakage into the skin (n = 6). (G) Representative Toluidine blue staining and quantification of cells with positive staining for Toluidine blue of skin tissue sections of DNP-treated WT and DCIR–/– mice (n = 6). Scale bar: 100 μm. (H) Heatmap of fold changes relative to the WT untreated group for the multiplex assays of cytokines and chemokines in supernatants of BMMCs from WT and DCIR–/– mice (n = 6). (I) ELISA analyses of cytokines and chemokines in supernatants of BMMCs from WT and DCIR–/– mice (n = 6). Data represent mean ± SEM of 2 independent experiments. Data were compared using a 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001.