Cellular and molecular mechanisms of TNF (tumor necrosis factor-alpha) mediated protection in atopic dermatitis

• Applicant: Professorin Dr. Margitta Worm
• Subject Area: Dermatology
• Term: from 2012 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 209252155

Atopic dermatitis (AD) represents a highly prevalent inflammatory skin disorder. Despite intense research efforts, its underlying pathophysiology remains poorly defined due to its highly complex nature. We previously discovered that contrast to its pro-inflammatory quality, tumor-necrosis factor-alpha (TNF) could actually protect from AD. TNFs counter-regulatory role was linked to its interference with thymic stromal lymphopoietin (TSLP) and mast cell (MC) hyperplasia. Speculating that these are key inter-related elements that determine AD severity, we have gathered solid evidence during the first funding period to demonstrate that the hypotheses are correct. Accordingly, interference with TSLP or MCs abrogated AD, dampened transepidermal water loss, and normalized expression of epidermal genes. With this prolongation we seek to obtain the ultimate proof of these connections through double-transgenic strategies. Having determined that MC secretory products possess TSLP-promoting activity and that MC tryptase is vital in this scenario, exploration of this mechanism will continue, including its validity in human skin. Finally, the molecular deregulations causing MC hyperplasia will be addressed. Recent findings indicate that TSLP itself may control MC survival, creating a positive feed-forward loop. After successful completion, the project will provide intriguing novel insights into the molecular network behind AD and plausibly permit more targeted treatments in a patient-tailored fashion.

• DFG Programme: Research Grants