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.

屋尘螨（HDM）是引起过敏性疾病（如特应性皮炎）的主要变应原。但是，对HDM诱导的免疫反应的调节机制尚未完全了解。NC / Nga小鼠是近交系，与其他品系相比，更容易受到HDM的影响，并发展出更严重的皮炎。使用全外显子组测序，我们发现NC / Nga小鼠在Clec10a中携带终止增益突变，该突变编码C型凝集素受体Clec10a（MGL1 / CD301a）。使用CRISPR-Cas9系统对该基因突变的修复改善了HDM诱导的皮炎，表明Clec10a突变是NC / Nga小鼠对HDM超敏的原因。同样，Clec10a ^-/-以C57BL / 6J为背景的小鼠表现出加重的HDM诱导的皮炎。在皮肤巨噬细胞上表达的Clec10a通过其细胞质部分的抑制性免疫受体酪氨酸激活基序，抑制了HDM诱导的Toll样受体4（TLR4）介导的炎性细胞因子的产生。我们确定无唾液酸糖蛋白受体1（Asgr1）为人类小鼠Clec10a的功能同源物。此外，我们发现HDM中的粘蛋白样分子是小鼠Clec10a和人Asgr1的配体。配体的皮肤施用改善了TLR4配体诱导的小鼠皮炎。我们的发现表明，小鼠的Clec10a和人类的Asgr1在皮肤稳态中可有效地抵抗与HDM诱发的皮炎相关的炎症。