4. DISCUSSION
4.5 CONCLUSION AND OUTLOOK
The epidermis is a rigid layer of the skin protecting an organism against external insults. It is also the anatomical structure to provide the skin barrier. An alteration of 84
the skin barrier initiates inflammatory processes which may lead to skin diseases. In this thesis it has been investigated how TSLP is regulated either after exposure to external irritants or in AD; a chronic inflammatory skin disease.
The data show that TSLP was rapidly induced in keratinocytes upon irritant exposure. Moreover skin perturbation of different kinds led to TSLP production starting from injury to chemical exposure. These data suggest that TSLP is one of the alarm signals in the skin upon exposure to any trauma. The mechanistic analysis revealed that though exogenous TNF-α was capable of inducing TSLP in vitro or ex vivo, endogenous TNF-α failed to do so. IL-1 a well known responder upon irritation, was partially involved in SDS mediated TSLP production. As the cascade of TSLP regulation and its role in irritation is still not very clear, further extensive work is required to pin point the different factors involved. To this end, skin biopsies and keratinocytes will be treated with different inhibitors or neutralizing antibodies or agonists and their antagonists.
To better understand the role of TNF-α in AD, an allergen dependent mouse dermatitis model was used. It showed an increased AD severity in TNF-/- compared to wt mice. Further analysis of these mice including the skin and serum revealed no major alterations of single cell types or factors except the TSLP expression locally and systemically and increased mast cell numbers in the skin which correlated with the clinical severity. As TNF-/- mice expressed more TSLP, it was important to understand the role of TSLP for the progression of AD. To achieve this goal, anti-TSLP was administered to neutralize the anti-TSLP mediated effects in eczema. Such treated mice showed a pronounced improvement of the AD, including a reduction of the TEWL. These findings indicate that TSLP is most likely a key cytokine in severe AD development under TNF deficiency. These data should be confirmed using TNF
-/-TSLP-/- double knockout mice to prove the role of TSLP in this scenario.
We observed an increase of the mast cell frequency which correlates with the symptom score and TSLP expression. The application of an anti cKit to the TNF -/-mice showed a reduction of eczema severity, indicating that mast cells are involved in AD in this model.
85
As previous data pointed out the role of mast cells in AD progression, the question arose whether mast cells can directly induce TSLP as they are known to produce TSLP210 or whether they can instruct keratinocytes to produce TSLP during AD progression as they are also known to instruct epithelial cells to produce TSLP133. In our hand data from BMcMcs have suggested that mast cells are not able to produce TSLP upon activation with anti IgE in combination with different proinflammatory cytokines. These results suggest that mast cells can instruct KCs to produce TSLP in TNF-/- mice during AD development. To confirm this hypothesis, we stimulated the skin biopsies with mast cell supernatants from stimulated and resting mast cells.
Supernatants from stimulated mast cells show no effect whereas the supernatants from resting mast cells were capable to stimulate the cells from skin biopsies to produce TSLP at significant levels. Next we tried to investigate which mast cell mediator is responsible for the instruction of KCs to produce TSLP. Surprisingly
‘histamine’ the most abundant mast cell mediator was not able to induce TSLP production. By contrast, we detected a significant increase of TSLP expression upon treatment with the mast cell protease “mMCP6”. In the future it needs to be confirmed whether tryptase is the main component of the MC supernatant triggering TSLP production in the skin. Such conformation would be possible if mMCP6-/- mice will be used in further experiments. Finally to confirm that mast cells are playing a role by instructing KCs to produce TSLP in enhancement of AD under TNF deficiency we need to perform the AD patch-model in mMCP6-/-TNF-/-TSLPR-/- triple knockout mice.
Irritation and inflammation of the skin is a complex process including the interplay of resident skin cells like KC and MC. Both TNF-α and TSLP contribute to this interplay in this scenario with a significant extend. Mouse skin models can help to better understand this complex network by applying knockout mice models or targeting key effector mediator in appropriate disease models.
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