New insight into atopic dermatitis development
New, interdisciplinary research between the University of Pennsylvania’s (UPenn) School of Dental Medicine, Perelman School of Medicine, and Oak Ridge National Laboratory, has highlighted how a cascade of inflammatory signalling is behind the lesions developed in atomic dermatitis. The inflammatory disease – affecting both adults and children – was previously thought to be caused by a breakdown in the barrier function of the skin.
It all began when research students in the Dentistry programme at UPenn noticed mice developing skin lesions when they had been genetically engineered to lack an inflammatory response.
[The mouse model was initially developed to study the role of inflammatory signaling in bone fracture healing in diabetes. The model was designed sans an activator of nuclear factor kappa-B (NF-kB), a master regulator of inflammatory responses. The activator in question is called IKKB.]
To better understand what was driving the development of the skin lesions, the research students sought expertise from the Dermatology Department. Professor of dermatology Dr. John Seykora and colleagues noted several features similar to human atopic dermatitis: in particular, they noted skin thickening and an infiltration of certain types of white blood cells.
Further analysis with computational systems biology experts from Oak Ridge National Laboratory revealed the exact cell type that was responsible for these effects – fibroblasts, a major structural component of the skin’s dermis layer.
Though NF-kB typically promotes inflammation, here, decreased NF-kB activity was paradoxically leading to recruitment of immune cells and associated inflammation. Data pointed to a protein transcription factor called CEBPB as being strongly activated in the fibroblasts lacking IKKB.
Another signalling molecule, CCL11, was likewise highly active in these fibroblasts; also known as eotaxin, CCL11 is a signaling molecule that promotes inflammation by recruiting a class of white blood cells called eosinophils, to its location.
When the team compared what they had seen in the mouse cells to skin samples of human tissue, they found similar patterns; CCL11 and CEBPB were both found at higher levels in affected skin samples than in unaffected skin. Levels of CCL11 also rose dramatically in additional experiments conducted with human skin fibroblasts, using an inhibitor to IKKB.
The research eventually led to the chance discovery of using monoclonal antibodies to tamp down the inflammatory responses in mice lacking IKKB – the pathway could be a new therapeutic target to reduce atopic dermatitis-associated inflammation.
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