Andreas Elentner

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‐γ 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.

Modulation of T Lymphocyte Function by the Pregnane X Receptor

The pregnane X receptor (PXR) is a ligand-activated transcription factor regulating genes central to drug and hormone metabolism in the liver. Previous reports indicated that PXR is expressed in PBMC, but the role of PXR in immune cells remains unknown. In this paper, we report increased PXR expression in mouse and human T lymphocytes upon immune activation. Furthermore, pharmacologic activation of PXR inhibits T lymphocyte proliferation and anergizes T lymphocytes by decreasing the expression of CD25 and IFN-γ and decreasing phosphorylated NF-κB and MEK1/2. Although these effects are preceded by an increase of suppressor of cytokine signaling 1, a master switch for IFN-γ expression, in a PXR-dependent manner, T-bet expression remains unchanged. Conversely, PXR-deficient mice exhibit an exaggerated T lymphocyte proliferation and increased CD25 expression. Furthermore, PXR-deficient lymphocytes produce more IFN-γ and less of the anti-inflammatory cytokine IL-10. In summary, these results reveal a novel immune-regulatory role of PXR in T lymphocytes and identify suppressor of cytokine signaling 1 as an early signal in PXR-mediated T lymphocyte suppression.

Peroxisome Proliferator-Activated Receptor-α Activation Inhibits Langerhans Cell Function

Epidermal Langerhans cells (LC) play a pivotal role in initiating and maintaining primary immune responses in the skin. In the present study, we asked whether peroxisome proliferator-activated receptor-α (PPARα) activation modulates LC function. Our results show that PPARα is expressed in immature LC and is down-regulated in mature LC suggesting that an early decrease of PPARα expression in LC may allow them to mature after contact with an Ag. We further show that pharmacologic PPARα activation inhibits LC maturation, migratory capacity, cytokine expression, and the ability to drive T cell proliferation. Moreover, PPARα activation inhibits NF-κB but not stress-activated protein kinase/JNK, p38MAPK, and ERK1/2. In conclusion, PPARα activation by endogenous ligands may provide a molecular signal that allows LC to remain in an immature state within the epidermis for extended periods of time despite minor environmental stimuli.

Lack of IL‐2 in PPAR‐α‐deficient mice triggers allergic contact dermatitis by affecting regulatory T cells

The aim of the present work was to decipher the cellular basis of the immunoregulatory role of peroxisome proliferator‐activated receptor (PPAR)‐α in cutaneous hypersensitivity reactions. After challenge with a contact allergen, we observed augmented hypersensitivity reactions with increased numbers of activated T lymphocytes in the skin of PPAR‐α−/− mice. Furthermore, following antigen challenge, the percentages of Tregs in the blood, draining lymph nodes and skin were decreased in these mice. PPAR‐α deficiency impaired the production of IL‐2 in lymph nodes, whereas TGF‐β levels remained unchanged. Injection of IL‐2 into PPAR‐α−/− mice restored the Treg population in the skin‐draining lymph nodes of allergen‐challenged mice. In vivo induction of Tregs from WT CD4+CD25− T cells was impaired when adoptively transferred into PPAR‐α−/− mice as compared with transfer into WT mice, and reversed by injection of IL‐2 into PPAR‐α−/− mice. Furthermore, the suppressive capacity of PPAR‐α−/− Tregs was impaired when compared to WT Tregs in vitro and in co‐adoptive transfer experiments. Finally, injection of IL‐2 to PPAR‐α−/− mice decreased skin inflammation to a level similar to WT mice. In conclusion, the pro‐inflammatory skin phenotype of PPAR‐α−/− mice is due to lack of IL‐2‐mediated Treg induction in these mice.

Skin response to a carcinogen involves the xenobiotic receptor pregnane X receptor.

Skin is in daily contact with potentially harmful molecules from the environment such as cigarette smoke, automobile emissions, industrial soot and groundwater. Pregnane X receptor (PXR) is a transcription factor expressed in liver and intestine that is activated by xenobiotic chemicals including drugs and environmental pollutants. Topical application of the tumor initiator 7,12‐dimethylbenz(a)anthracene (DMBA) enhances Pxr, Cyp1a1, Cyp1b1 and Cyp3a11, but not Ahr expression in the skin. Surprisingly, DMBA‐induced Pxr upregulation is largely impaired in Langerin+ cell‐depleted skin, suggesting that DMBA mainly triggers Pxr in Langerin+ cells. Furthermore, PXR deficiency protects from DNA damage in epidermal cells but to a lesser extent than aryl hydrocarbon receptor (AHR) deficiency. Interestingly, skin exposure to low doses of DMBA induces migration of PXR‐deficient but not of wild‐type and AHR‐deficient Langerhans cells (LCs). PXR‐humanized mice show a marked increase in DNA damage to epidermal cells after topical application of DMBA, demonstrating relevance of these findings in human tissue. This is the first report suggesting that carcinogens might trigger PXR in epidermal cells, particularly in LCs, thus leading to DNA damage. Further studies are required to better delineate the role of PXR in cutaneous carcinogenesis.

Epidermal overexpression of xenobiotic receptor PXR impairs the epidermal barrier and triggers Th2 immune response

The skin is in daily contact with environmental pollutants, but the long-term effects of such exposure remain underinvestigated. Many of these toxins bind and activate the pregnane X receptor (PXR), a ligand-activated transcription factor that regulates genes central to xenobiotic metabolism. The objective of this work was to investigate the effect of constitutive activation of PXR in the basal layer of the skin to mimic repeated skin exposure to noxious molecules. We designed a transgenic mouse model that overexpresses the human PXR gene linked to the herpes simplex VP16 domain under the control of the keratin 14 promoter. We show that transgenic mice display increased transepidermal water loss and elevated skin pH, abnormal stratum corneum lipids, focal epidermal hyperplasia, activated keratinocytes expressing more thymic stromal lymphopoietin, a T helper type 2/T helper type 17 skin immune response, and increased serum IgE. Furthermore, the cutaneous barrier dysfunction precedes development of the T helper type 2/T helper type 17 inflammation in transgenic mice, thereby mirroring the time course of atopic dermatitis development in humans. Moreover, further experiments suggest increased PXR signaling in the skin of patients with atopic dermatitis when compared with healthy skin. Thus, PXR activation by environmental pollutants may compromise epidermal barrier function and favor an immune response resembling atopic dermatitis.