Role of keratinocyte-derived TRPV4 ion channel in inflammation, pain and pruritus - epidermal-neuronal communication

• Applicant: Dr. Mathias Sulk
• Subject Area: Dermatology
• Term: from 2013 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 240302291

Keratinocytes are critical cells for a functional barrier protection of our body system. They detect harmful (physical, chemical, biological) stimuli and communicate with sensory nerves and immune cells to induce responses which prevent potentially life-threatening tissue damage. UV radiation has been implicated in inflammatory processes leading to immune responses and pain by inducing an increased communication between keratinocytes, immune cells and sensory nerves. Our preliminary data indicate an important role of Transient receptor potential ion channel TRPV4 during acute photodermatitis ('sunburn'). TRPVs are expressed by sensory nerves and keratinocytes and are important homeostatic regulators. Neuronal TRPV4 functions as an osmo- and mechanosensor and is able to mediate neurogenic inflammation. However, the exact role of keratinocyte-specific TRPV4 is poorly understood. I will use immunohistological, molecular and electrophysiological approaches as well as in vivo and in vitro experiments to investigate the role of TRPV4 in inflammatory skin diseases to test my hypothesis that epidermally-expressed TRPV4 is an important communication pathway between keratinocytes and cutaneous sensory nerve fibers during acute inflammation, pain or pruritus. In the labs of Prof. A. Basbaum (in collaboration with Prof. L. Ptacek and Prof. M. Steinhoff) I will characterize the immunological and nerval pathways which underlie acute inflammatory responses and pruritus modulation in conditional keratinocyte-specific TRPV4 knockout mice. Therefore my aims are to test the following hypotheses: 1. Keratinocyte-TRPV4 mediates inflammation and pruritus in murine models of acute and chronic dermatitis, 2. TRPV4 activation of murine keratinocytes induces release of mediators that activate murine dorsal root ganglia and are involved in neurogenic inflammation and itch, and 3. activation of keratinocyte-derived TRPV4 induces neuronal responses in sensory nerves in vivo. Altogether this research project aims to reveal new findings in the mechanisms of epidermal-neuronal communication.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Allan Basbaum