Infiltration and local differentiation of bone marrow–derived integrinβ7-positive mast cell progenitors in atopic dermatitis–like skin

Background Mast cells (MCs) are tissue-resident cells with various immunologic functions. MCs are increased in atopic dermatitis (AD) skin and can contribute to the inflammation. Although skin MCs are inducible from bone marrow (BM) cells in vitro, they are maintained locally by self-proliferation in the steady state in vivo. However, how skin MCs are increased in AD skin, including the infiltration of BM-derived MC progenitors (MCps) and their differentiation, remains unclear. Objective We sought to identify and characterize BM-derived MCps in AD skin. Methods BM-derived MCps in AD skin were analyzed by flow cytometry using BM-chimeric mice and parabiosis in an MC903-induced AD model. BM-derived MCps in AD-like skin were compared with resident MCs for gene expression by RNA- sequencing analysis. Results We observed local proliferation of resident MCs and an increase in BM-derived MCs in AD-like skin. BM-derived MCs in the skin were derived from circulating MCps and were distinguishable from resident MCs by integrinβ7. RNA- sequence analysis showed that integrinβ7+ MCs (BM-derived MCps) in the skin shared the characteristics of both mucosal-type MCs and connective tissue–type MCs, and increased the expression of genes related to MCp migration. BM-derived MCps proliferated in situ, gradually lost the integrinβ7 expression, and acquired connective tissue–type MC phenotypes during the remission phase of inflammation. Conclusions BM-derived integrinβ7+ MCps migrate to AD-like skin and contribute to the maintenance of skin MCs. Mast cells (MCs) are tissue-resident cells with various immunologic functions. MCs are increased in atopic dermatitis (AD) skin and can contribute to the inflammation. Although skin MCs are inducible from bone marrow (BM) cells in vitro, they are maintained locally by self-proliferation in the steady state in vivo. However, how skin MCs are increased in AD skin, including the infiltration of BM-derived MC progenitors (MCps) and their differentiation, remains unclear. We sought to identify and characterize BM-derived MCps in AD skin. BM-derived MCps in AD skin were analyzed by flow cytometry using BM-chimeric mice and parabiosis in an MC903-induced AD model. BM-derived MCps in AD-like skin were compared with resident MCs for gene expression by RNA- sequencing analysis. We observed local proliferation of resident MCs and an increase in BM-derived MCs in AD-like skin. BM-derived MCs in the skin were derived from circulating MCps and were distinguishable from resident MCs by integrinβ7. RNA- sequence analysis showed that integrinβ7+ MCs (BM-derived MCps) in the skin shared the characteristics of both mucosal-type MCs and connective tissue–type MCs, and increased the expression of genes related to MCp migration. BM-derived MCps proliferated in situ, gradually lost the integrinβ7 expression, and acquired connective tissue–type MC phenotypes during the remission phase of inflammation. BM-derived integrinβ7+ MCps migrate to AD-like skin and contribute to the maintenance of skin MCs.