Clec10a regulates mite-induced dermatitis
Clec10a regulates mite-induced dermatitis
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DOI：
10.1126/sciimmunol.aax6908
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发表时间：
2019-12-01
影响因子：
24.8
通讯作者：
Shibuya, Akira
中科院分区：
文献类型：
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作者：
Kanemaru, Kazumasa;Noguchi, Emiko;Shibuya, Akira
屋尘螨（HDM）是引起过敏性疾病如特应性皮炎的主要过敏原。然而，HDM诱导的免疫应答的调节机制还不完全清楚。NC/Nga小鼠是一种近交系小鼠，比其他品系小鼠更易患HDM，并发生更严重的皮炎。使用全外显子组测序，我们发现NC/Nga小鼠在Clec 10a中携带停止增益突变，该突变编码C型凝集素受体Clec 10a（MGL 1/CD 301 a）。使用CRISPR-Cas9系统修复该基因突变改善了HDM诱导的皮炎，表明Clec 10a突变是NC/Nga小鼠对HDM超敏反应的原因。类似地，C57 BL/6 J背景的Clec 10a（-/-）小鼠显示出加重的HDM诱导的皮炎。在皮肤巨噬细胞上表达的Clec 10a通过其细胞质部分中的抑制性免疫受体酪氨酸激活基序抑制HDM诱导的Toll样受体4（TLR 4）介导的炎性细胞因子产生。我们确定了去唾液酸糖蛋白受体1（Asgr 1）作为一个功能同源的小鼠Clec 10a在人类。此外，我们发现HDM中的粘蛋白样分子是小鼠Clec 10a和人Asgr 1的配体。皮肤应用的配体改善了TLR 4配体诱导的小鼠皮炎。我们的研究结果表明，小鼠中的Clec 10a和人类中的Asgr 1在皮肤稳态中对与HDM诱导的皮炎相关的炎症起着重要作用。
House dust mite (HDM) is a major allergen that causes allergic diseases such as atopic dermatitis. However, the regulatory mechanisms of HDM-induced immune responses are incompletely understood. NC/Nga mice are an inbred strain that is more susceptible to HDM and develops more severe dermatitis than other strains. Using whole-exome sequencing, we found that NC/Nga mice carry a stop-gain mutation in Clec10a, which encodes a C-type lectin receptor, Clec10a (MGL1/CD301a). The repair of this gene mutation using the CRISPR-Cas9 system ameliorated HDM-induced dermatitis, indicating that the Clec10a mutation is responsible for hypersensitivity to HDM in NC/Nga mice. Similarly, Clec10a(-/-) mice on the C57BL/6J background showed exacerbated HDM-induced dermatitis. Clec10a expressed on skin macrophages inhibits HDM-induced Toll-like receptor 4 (TLR4)-mediated inflammatory cytokine production through the inhibitory immunoreceptor tyrosine activating motif in its cytoplasmic portion. We identified asialoglycoprotein receptor 1 (Asgr1) as a functional homolog of mouse Clec10a in humans. Moreover, we found that a mucin-like molecule in HDM is a ligand for mouse Clec10a and human Asgr1. Skin application of the ligand ameliorated a TLR4 ligand-induced dermatitis in mice. Our findings suggest that Clec10a in mice and Asgr1 in humans play an important role in skin homeostasis against inflammation associated with HDM-induced dermatitis.