Research ArticleALLERGY

Clec10a regulates mite-induced dermatitis

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Science Immunology  06 Dec 2019:
Vol. 4, Issue 42, eaax6908
DOI: 10.1126/sciimmunol.aax6908

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Dermatitis details

House dust mite (HDM) is an allergen associated with a variety of diseases, including asthma and atopic dermatitis (AD). The NC/Nga mouse strain develops severe AD in response to HDM, and Kanemaru et al. have now identified a stop-gain mutation, the Clec10a C-type lectin receptor, that is associated with this response. HDM-induced dermatitis was driven by TLR4-mediated inflammatory responses, and asialoglycoprotein receptor 1 (Asgr1) functions as a Clec10a homolog in humans. They also identified a mucin-like molecule in HDM that can function as a ligand for Clec10a and Asgr1. These results provide insight into mechanisms associated with HDM-mediated dermatitis.

Abstract

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.

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