Abstract
Atopic dermatitis (AD) is a complex, often lifelong allergic disease with severe pruritus affecting around 10% of both humans and dogs. To investigate the role of mast cells (MCs) and MC-specific proteases on the immunopathogenesis of AD, a vitamin D3-analog (MC903) was used to induce clinical AD-like symptoms in c-kit-dependent MC-deficient Wsh−/− and the MC protease-deficient mMCP-4−/−, mMCP-6−/−, and CPA3−/− mouse strains. MC903-treatment on the ear lobe increased clinical scores and ear-thickening, along with increased MC and granulocyte infiltration and activity, as well as increased levels of interleukin 33 (IL-33) locally and thymic stromal lymphopoietin (TSLP) both locally and systemically. The MC-deficient Wsh−/− mice showed significantly increased clinical score and ear thickening albeit having lower ear tissue levels of IL-33 and TSLP as well as lower serum levels of TSLP as compared to the WT mice. In contrast, although having significantly increased IL-33 ear tissue levels the chymase-deficient mMCP-4−/− mice showed similar clinical score, ear thickening, and TSLP levels in ear tissue and serum as the WT mice, whereas mMCP-6 and CPA3 -deficient mice showed a slightly reduced ear thickening and granulocyte infiltration. Our results suggest that MCs promote and control the level of MC903-induced AD-like inflammation.
Highlights
Atopic dermatitis (AD) develops after inflammatory responses against common environmental antigens (Ag) and is a lifelong disease with approximately 10 to 15% prevalence in both children and dogs [1,2]
I.e., on day 14 of treatment, these changes had developed into clearly visible thickening and dryness of the skin of the MC903-treated mice (Figure S1a) and all MC903-treated ears had at least a clinical score of 1, which corresponds to mild redness and swelling
The low dose of MC903 induced inflammatory changes in all mouse strains studied, similar to those seen in human and canine AD-patients, confirming the use of a low dose of MC903 to create a functioning mouse model of AD
Summary
Atopic dermatitis (AD) develops after inflammatory responses against common environmental antigens (Ag) and is a lifelong disease with approximately 10 to 15% prevalence in both children and dogs [1,2]. The pruritus is usually followed by typical lesions, such as erythematous macules and flaky skin with comparable symptoms in humans and dogs [1,4,5]. These early lesions aggravate into chronic lesions with hyperpigmentation and lichenification due to self-trauma, and hyperplasia of the epidermis and corresponding thickening of the skin is a typical histological finding in the skin lesions of AD patients [6,7,8]. MCs can act directly against environmental allergens and can play a key role in driving the immune response against a not so harmful Ag, e.g., house dust mite allergens, which causes the allergic reactions that develop into AD in both canines and humans [14,15]
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