House dust mites activate nociceptor-mast cell clusters to drive type 2 skin inflammation

Abstract

Allergic skin diseases, such as atopic dermatitis (AD), are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely-distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine-protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons, that expressed the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDMs-activated nociceptors drove the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors through the release of substance P and the activation of the cationic molecules receptor MRGPRB2 on mast cells. This data indicates that, after exposure to HDM allergens, activation of TRPV1 ⁺ Tac1 ⁺ nociceptor-MRGPRB2 ⁺ sensory clusters represents a key early event in the development of allergic skin reaction.