Dendritic cell immunoreceptor drives atopic dermatitis by modulating oxidized CaMKII-involved mast cell activation.
Dendritic cell immunoreceptor drives atopic dermatitis by modulating oxidized CaMKII-involved mast cell activation.
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DOI：
10.1172/jci.insight.152559
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发表时间：
2022-03-08
期刊：
影响因子：
8
通讯作者：
Gao P
中科院分区：
文献类型：
--
作者：
Luo X;Chen J;Yang H;Hu X;Alphonse MP;Shen Y;Kawakami Y;Zhou X;Tu W;Kawakami T;Wan M;Archer NK;Wang H;Gao P
过敏原已被确定为特应性皮炎（AD）患者的潜在触发因素。AD患者对蟑螂过敏原高度敏感。然而，其内在机制仍不确定。在这里，我们建立了一个蟑螂过敏原诱导的AD样小鼠模型，我们证明，反复暴露于蟑螂过敏原导致小鼠皮肤炎症加重，其特征是增加2型免疫，2型先天淋巴细胞（ILC 2），和肥大细胞。在AD患者中也观察到肥大细胞增加。肥大细胞缺陷小鼠（KitW-sh/W-sh）显示皮肤炎症减少，表明肥大细胞在过敏原诱导的皮肤炎症中是必需的。此外，DC免疫受体（DCIR）在AD患者的皮肤肥大细胞中上调，并介导过敏原结合和摄取。DCIR-/-小鼠或用DCIR-/-肥大细胞重建的KitW-sh/W-sh小鼠显示AD样炎症显著减少。体外和体内分析均表明DCIR-/-肥大细胞具有降低的IgE介导的肥大细胞活化和被动皮肤过敏反应。从机制上讲，DCIR调节变应原诱导的IgE介导的肥大细胞ROS生成和钙调蛋白激酶II（ox-CaMKII）的氧化。抗ROS CaMKII（MM-VVδ）可防止过敏原诱导的肥大细胞活化和炎症介质释放。我们的研究揭示了DCIR/ROS/CaMKII轴控制过敏原诱导的肥大细胞活化和AD样炎症。
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.
影响因子：
3.7
作者：
Tsai YM;Hsu SC;Zhang J;Zhou YF;Plunkett B;Huang SK;Gao PS
通讯作者：
Gao PS
DOI：
10.1084/jem.20071391
发表时间：
2007-11-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Zhou JS;Xing W;Friend DS;Austen KF;Katz HR
通讯作者：
Katz HR