Atopic dermatitis (AD) is a chronic relapsing inflammatory disease of the skin, characterized by pruritus (severe itching of the skin), eczema, and hypersensitivity to innocuous environmental substances, which affects 10- 20% of children worldwide. The etiology of AD is incompletely understood, but various types of immune or structural cells and multiple cell signaling pathways are thought to contribute to the development of skin lesions and immunological abnormalities in AD. The skin is a complex organ containing a large population of mast cells (MCs) and innervated by an intricate network of abundant sensory nerve fibers, including ?nociceptors? ? sensory nerves that are activated by harmful or potentially dangerous stimuli. Recent findings suggest that subtypes of nociceptive sensory neurons, by importantly influencing specialized immune cells, can regulate the development of both protective and pathogenic responses. Other recent studies have shown that mouse skin MCs exhibit strong expression of genes encoding receptors in the Mas-related G protein-coupled receptors (MRGPR) family (e.g., Mrgprb2: the receptor for the substance P [SP] in the mouse), through which MCs might uniquely interact with nociceptors. The central hypothesis of this project is that interactions between Trpv1+, Tac1+ (i.e., SP-producing) nociceptors and Mrgprb2+ MCs play a critical role in the development of the skin pathology and immunological abnormalities associated with type 2 skin inflammation. This hypothesis is based on the following preliminary findings: (1) TRPV1 gene expression is increased in the skin of AD patients. (2-4) Using a mouse model of AD, in which epicutaneous exposure to Dermatophagoides farinae extract (Der f) and staphylococcal enterotoxin B (SEB) induces a dermatitis whose skin pathology and gene expression pattern are similar to those in human AD, we found that: (2) Trpv1+ nociceptors and MCs, as well as expression of the Tac1 gene (encoding the precursor for SP), are required for dysregulation of claudin 1 structure, development of AD-like skin lesions, and production of Der f-specific IgG1 and IgE; (3) dermal MCs physically interact with skin SP+ nociceptors; and (4) MCs and Mrgprb2 are required for SP-induced skin inflammation. We now wish to extend these observations and explore their translational relevance by using state-of-the-art genetic and cell transfer studies in mice to understand the mechanisms of nociceptor/MC cross-talk in the development of AD skin pathology, impaired barrier function, and immunological abnormalities, and to use innovative imaging approaches to analyze and compare nociceptor/MC interactions in lesional skin of mice and in humans with AD. We think that the proposed studies will provide new insights into skin neuro-immune interactions that can influence type 2 skin inflammation, particularly those reflecting interactions between SP-producing peptidergic nociceptors and MCs, both in a mouse model of AD and in lesional skin of patients with AD. Accordingly, our findings have the potential to identify new therapeutic targets for treating AD and perhaps other type 2 skin disorders.
Atopic dermatitis (AD), or eczema, is a chronic, pruritic (very itchy) inflammatory skin disease with major health and social impacts and costs. The incidence of this disease has been increasing for the last three decades and it now affects at least 15% of children. This proposal seeks to identify the molecular mechanisms underlying the development of AD, and to determine whether interactions between sensory nerves and mast cells in the skin both contribute to the pathology of AD and represent a potential new therapeutic target in this disorder.
|Mukai, Kaori; Tsai, Mindy; Saito, Hirohisa et al. (2018) Mast cells as sources of cytokines, chemokines, and growth factors. Immunol Rev 282:121-150|