Molecular Mechanisms of Itch Signaling in Keratinocytes
- Author(s): The, Lydia
- Advisor(s): Bautista, Diana
- et al.
There is accumulating evidence suggesting that keratinocytes, the predominant cell type in the skin, may play a key role in the transduction of several somatosensory modalities, including itch. Keratinocytes are activated by a number of itch compounds and release a variety of molecules associated with itch. Additionally, itch-transducing neurons terminate as free nerve endings in the keratinocyte layer of the skin, which would permit rapid keratinocyte-neuron signaling. Our work has focused on two areas: 1) defining the molecular mechanisms by which the atopic dermatitis cytokine TSLP is released from keratinocytes and act on neurons to cause itch and 2) identifying the distinct mechanisms by which histamine and protease signaling in keratinocytes triggers itch.
Previous studies have shown that activation of the Protease-Activated Receptor 2 (PAR2) leads to upregulation of TSLP in keratinocytes and that TSLP overexpression in keratinocytes induces chronic itch in mice. We characterized the mechanisms by which PAR2 activation leads to TSLP expression and secretion, and elucidated the mechanisms by which secreted TSLP in the skin leads to itch. Understanding the molecular mechanisms underlying atopic dermatitis may identify targets that could lead to the development of drugs that specifically block atopic dermatitis itch while leaving other somatosensations intact.
Previous studies have linked histamine and protease signaling to distinct clinical itch phenotypes; histamine signaling is associated with allergic itch, while protease signaling is associated with atopic dermatitis. Histamine and PAR2 agonists activate the same population of keratinocytes, thus how these pruritogens trigger distinct itch pathologies was unknown. We now demonstrate that histamine and protease signaling in keratinocytes induce distinct calcium signals that lead to divergent downstream transcriptional outputs.