Mast Cells Limit Ear Swelling Independently of the Chymase Mouse Mast Cell Protease 4 in an MC903-Induced Atopic Dermatitis-Like Mouse Model

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.

Novel Insights Into the Immune-Regulatory Functions of Mast Cells in the Cutaneous Immune Response

“…Since the ratio of activated T cells to Tregs in the skin was significantly higher in Kit W-sh/W-sh mice reconstituted with Il2 -/- MCs than in those reconstituted with WT MCs, it was concluded that MCs inhibit dermatitis by maintaining Tregs via IL-2 production ( 19 ). Exacerbated phenotypes in Kit W-sh/W-sh mice have also been reported in the MC903-induced AD model ( 36 ), but the underlying mechanisms by which MCs suppress inflammation in this model remain unclear.…”

Glial Cells and Itch: Possible Targets for Novel Antipruritic Therapies

“…As an alarmin cytokine, IL-33 is crucial for the development of skin diseases. , Studies using the conditional knockout of St2 in sensory neurons have revealed that sensory-neuron-restricted ST2 signaling is a critical regulator of itch in dry skin mice . Moreover, IL-33 has been shown to be upregulated in the inflamed skin and regulate chronic itch in MC903-induced AD-like mice and urushiol-challenged ACD itchy mice. , …”

Roles of Mast Cells in Cutaneous Diseases

“…MC903-induced dermatitis was dependent on thymic stromal lymphopoietin (TSLP), IL-25 and IL-33 in BALB/c mice ( 76 ), and on TSLP, but not IL-25 or IL-33, in C57BL/6 mice ( 77 ). Mast cells were involved in TSLP production and induction of skin inflammation in MC903-induced dermatitis ( 78 ).…”