Mast Cells Are Dispensable in a Genetic Mouse Model of Chronic Dermatitis

Abstract

Chronic inflammatory skin diseases, such as atopic dermatitis, affect a large percentage of the population, but the role of different immune cells in the pathogenesis of these disorders is largely unknown. Recently, we found that mice lacking fibroblast growth factor receptor 1 (Fgfr1) and Fgfr2 (K5-R1/R2 mice) in the epidermis have a severe impairment in the epidermal barrier, which leads to the development of a chronic inflammatory skin disease that shares many features with human atopic dermatitis. Using Fgfr1-/Fgfr2-deficient mice, we analyzed the consequences of the loss of mast cells. Mast cells accumulated and degranulated in the skin of young Fgfr1-/Fgfr2-deficient mice, most likely as a consequence of increased expression of the mast cell chemokine Ccl2. The increase in mast cells occurred before the development of histological abnormalities, indicating a functional role of these cells in the inflammatory skin phenotype. To test this hypothesis, we mated the Fgfr1-/Fgfr2-deficient mice with mast cell-deficient CreMaster mice. Surprisingly, loss of mast cells did not or only mildly affect keratinocyte proliferation, epidermal thickness, epidermal barrier function, accumulation and activation of different immune cells, or expression of different proinflammatory cytokines in the skin. These results reveal that mast cells are dispensable for the development of chronic inflammation in response to a defect in the epidermal barrier.

Accumulation and activation of epidermal γδ T cells in a mouse model of chronic dermatitis is not required for the inflammatory phenotype

“…Thus, mice lacking FGF receptors (FGFR) 1 and 2 in keratinocytes (K5-R1/R2 mice) show severe transepidermal water loss (TEWL) due to downregulation of tight junction components. As a consequence, they develop chronic dermatitis with strong similarities to AD [3,4]. Consistent with the mouse data, reduced expression of FGFR1 and FGFR2 was detected in the skin of AD patients [5], and single nucleotide polymorphisms in the FGFR1 and FGFR2 genes were linked to atopy [6].…”

“…Sections (7 μm) were stained with H&E or immunostained with anti-TCRδ-FITC antibody (clone GL3, BD Bioscience, Allschwill, Switzerland) or anti-TCRβ-PE antibody (clone H57-597, BD Bioscience) as described [3,4]. All analyses were performed blinded with regard to the genotype of the mice.…”

“…Isolated epidermis and dermis were immediately frozen in liquid nitrogen, and RNA was isolated using TRIzol [3,4].…”

“…TEWL was determined using a Tewameter (Courage and Khazaka Electronic GmbH, Cologne, Germany) as described previously [3,4].…”

“…Skin sections were analyzed by immunofluorescence (see above) using BrdU-FITC antibody (Roche, Rotkreuz, Switzerland) and 2 μg/mL propidium iodide as a counterstain [3,4].…”