Bone morphogenetic protein signaling regulates skin inflammation via modulating dendritic cell function,Journal of Allergy and Clinical Immunology

当前位置： X-MOL 学术 › J. Allergy Clin. Immunol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Bone morphogenetic protein signaling regulates skin inflammation via modulating dendritic cell function
Journal of Allergy and Clinical Immunology ( IF 11.4 ) Pub Date : 2020-10-22 , DOI: 10.1016/j.jaci.2020.09.038
Tommaso Sconocchia ₁ , Mathias Hochgerner ₂ , Elke Schwarzenberger ₁ , Carmen Tam-Amersdorfer ₁ , Izabela Borek ₁ , Theresa Benezeder ₃ , Thomas Bauer ₂ , Victoria Zyulina ₁ , Clemens Painsi ₄ , Christina Passegger ₁ , Peter Wolf ₃ , Maria Sibilia ₂ , Herbert Strobl ₁

Affiliation

Background

Bone morphogenetic proteins (BMPs) are members of the TGF-β family that signal via the BMP receptor (BMPR) signaling cascade, distinct from canonical TGF-β signaling. BMP downstream signaling is strongly induced within epidermal keratinocytes in cutaneous psoriatic lesions, and BMP7 instructs monocytic cells to acquire characteristics of psoriasis-associated Langerhans dendritic cells (DCs). Regulatory T (Treg)-cell numbers strongly increase during psoriatic skin inflammation and were recently shown to limit psoriatic skin inflammation. However, the factors mediating Treg-cell accumulation in psoriatic skin currently remain unknown.

Objective

We sought to investigate the role of BMP signaling in Treg-cell accumulation in psoriasis.

Methods

The following methods were used: immunohistology of patients and healthy controls; ex vivo models of Treg-cell generation in the presence or absence of Langerhans cells; analysis of BMP versus canonical TGF-β signaling in DCs and Treg cells; and modeling of psoriatic skin inflammation in mice lacking the BMPR type 1a in CD11c⁺ cells.

Results

We here demonstrated a positive correlation between Treg-cell numbers and epidermal BMP7 expression in cutaneous psoriatic lesions and show that unlike Treg cells from healthy skin, a portion of inflammation-associated Treg cells exhibit constitutive-active BMP signaling. We further found that BMPR signaling licenses inflammation-associated Langerhans cell/DC to gain an enhanced capacity to promote Treg cells via BMPR-mediated CD25 induction and that this effect is associated with reduced skin inflammation.

Conclusions

Psoriatic lesions are marked by constitutive high BMP7/BMPR signaling in keratinocytes, which instructs inflammatory DCs to gain enhanced Treg-cell–stimulatory activity. Locally secreted BMP7 can directly promote Treg-cell generation through the BMP signaling cascade.

中文翻译：

骨形态发生蛋白信号通过调节树突细胞功能调节皮肤炎症

背景

骨形态发生蛋白 (BMP) 是 TGF-β 家族的成员，通过 BMP 受体 (BMPR) 信号级联传递信号，与经典的 TGF-β 信号传导不同。BMP 下游信号在皮肤银屑病病变的表皮角质形成细胞内被强烈诱导，BMP7 指示单核细胞获得银屑病相关朗格汉斯树突细胞 (DC) 的特征。调节性 T (Treg) 细胞数量在银屑病皮肤炎症期间强烈增加，最近被证明可以限制银屑病皮肤炎症。然而，目前尚不清楚银屑病皮肤中介导 Treg 细胞积累的因素。

客观的

我们试图研究 BMP 信号在银屑病中 Treg 细胞积累中的作用。

方法

使用以下方法：患者和健康对照的免疫组织学；在存在或不存在朗格汉斯细胞的情况下 Treg 细胞生成的离体模型；DCs 和 Treg 细胞中 BMP 与经典 TGF-β 信号的分析；CD11c ⁺细胞中缺乏 BMPR 1a 型的小鼠的银屑病皮肤炎症模型。

结果

我们在这里证明了皮肤银屑病病变中 Treg 细胞数量和表皮 BMP7 表达之间的正相关性，并表明与来自健康皮肤的 Treg 细胞不同，一部分炎症相关的 Treg 细胞表现出组成型活性 BMP 信号。我们进一步发现，BMPR 信号允许炎症相关的朗格汉斯细胞/DC 获得增强的能力，通过 BMPR 介导的 CD25 诱导促进 Treg 细胞，并且这种作用与减少皮肤炎症有关。