Langerhans cells are critical in the development of atopic dermatitis-like inflammation and symptoms in mice.
Genetic or vitamin D3-induced overexpression of thymic stromal lymphopoietin (TSLP) by keratinocytes results in an atopic dermatitis (AD)-like inflammatory phenotype in mice echoing the discovery of high TSLP expression in epidermis from AD patients. Although skin dendritic cells (DC) are suspected to be involved in AD, direct evidence of a pathogenetic role for skin DC in TSLP-induced skin inflammation has not yet been demonstrated. In a mouse model of AD, i.e. mice treated with the low-calcemic vitamin D3 analogue, MC903, we show that epidermal Langerhans cells (LC)-depleted mice treated with MC903 do neither develop AD-like inflammation nor increased serum IgE as compared to vitamin D3 analogue-treated control mice. Accordingly, we show that, in mice treated with MC903 or in K14-TSLP transgenic mice, expression of maturation markers by LC is increased whereas maturation of dermal DC is not altered. Moreover, only LC are responsible for the polarization of naïve CD4(+) T cells to a Th2 phenotype, i.e. decrease in interferon-gamma and increase in interleukin (IL)-13 production by CD4(+) T cells. This effect of LC on T-lymphocytes does not require OX40-L/CD134 and is mediated by a concomitant down-regulation of IL-12 and CD70. Although it was previously stated that TSLP up-regulates the production of thymus and activation-regulated chemokine (TARC)/chemokine (C-C motif) ligand 17 (CCL17) and macrophage-derived chemokine (MDC)/CCL22 by human LC in vitro, our work shows that production of these Th2- cell attracting chemokines is increased only in keratinocytes in response to TSLP overexpression. These results demonstrate that LC are required for the development of AD in mouse models of AD involving epidermal TSLP overexpression.
Elentner
Andreas
A
Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.
Finke
Daniela
D
Developmental Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
Schmuth
Matthias
M
Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.
Chappaz
Stéphane
S
Developmental Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
Ebner
Susanne
S
Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.|Kompetenzzentrum Medizin Tirol / CEMIT, Innsbruck, Austria.
Malissen
Bernard
B
Centre d'Immunologie de Marseille-Luminy, Institut National de la Santé et de la Recherche Médicale Unité, Centre National de la Recherche Scientifique Unité Mixte de Recherche, Universite de la Mediterrannée, Marseille, France.
Kissenpfennig
Adrien
A
Center for cancer research and cell biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
Romani
Nikolaus
N
Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.|Kompetenzzentrum Medizin Tirol / CEMIT, Innsbruck, Austria.
Dubrac
Sandrine
S
Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria.
D000818:Animals; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007801:Langerhans Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D016133:Polymerase Chain Reaction