Key factors involved in skin inflammation discovered
MedWire News: Researchers have identified a cellular "gatekeeper" that when destroyed can trigger atopic dermatitis and myeloproliferative disorders.
"We knew that skin cells called keratinocytes direct the local immune response, yet the signaling networks in the skin that control the immune response were poorly defined," explained study author Rama Khokha (Ontario Cancer Institute, Toronto, Canada) in a press statement.
"In our study we investigated whether an enzyme called ADAM17 [a disintegrin and metalloproteinase 17] is involved in crosstalk between the skin and the immune system. ADAM17 sheds proteins from the cell surface and has been implicated in immune cell function and development."
The researchers deleted the gene encoding ADAM17 in the skin of adult mice and observed spontaneous production of inflammatory proteins by the keratinocytes as a consequence, resulting in inflammation of the skin and T-helper cell (2 and/or 17) proliferation.
Writing in the journal Immunity, Khokha and team report that Notch signalling was dampened in response to ADAM17 deficiency, both in vitro and in vivo, and resulted in increased production of the T-helper-cell 2 cell-polarising cytokine thymic stromal lymphoprotein, as well as the myeloid granulocyte colony-stimulating factor.
The Notch signalling pathway is associated with the maintenance of normal skin and has been shown to have a role in preventing inflammatory skin disease.
When Notch was reactivated in the skin of the mice, local skin inflammation decreased significantly and abnormal immune cell proliferation ceased.
"Our study provides the first demonstration of the physiological requirement of ADAM17 in Notch signaling and demonstrates that loss of this gatekeeper triggers an immune response, even in the absence of injury or infection," summarized Khokha.
"A better understanding of the mechanisms that regulate communication between immune and non-immune cells will be of significant value in the treatment of diseases affecting the skin and other barrier tissues."
By Helen Albert