Background & Aims

Keratinocytes are epithelial cells of the skin that have been appreciated to regulate sensory responses of itch and noxious pain. Here, we investigate the role of exogenous tetracycline transactivator in keratinocyte in regulating nociceptive behavior of pain and itch.

Methods

Using transgenic mice and novel chemogenetic methods, we measure murine behavior of scratching as well as other pain associated nocifensive behaviors. We investigate the requirements of TRPV1, as well as opioid receptors using chemical denervation as well as pharmacological interventions.

Results

Here we describe a profound itch phenotype in mice expressing a genetically encoded tetracycline transactivator (tTA) that is conditionally activated within the Phox2a lineage. Phox2a; tTA mice develop intense, localized scratching and regional skin lesions that can be controlled by the tTA inhibitor, doxycycline. As gabapentin, but not morphine, relieved the scratching, we consider this phenotype to result from chronic neuropathic itch, not pain. In contrast to the Phox2a lineage, mice with tTA activated within the Phox2b lineage, which has many similar areas of recombination within the nervous system, did not recapitulate the scratch. Keratinocyte driven expression of tTA with a K14 promoter lead to spontaneous and chronic scratching, confirming the keratinocyte contribution to pruritus. Repeated topical application of the DREADD agonist, CNO, which chronically induced Gi signaling in Phox2a-keratinocytes, completely reversed the localized scratching through a TRPV1 dependent manner.

Conclusions

These temporal properties suggest that the neuropathic itch condition arises not only from localized keratinocyte activation of peripheral nerves but also from a persistent, gabapentin-sensitive state of central sensitization.

References

Wilson SR, Thé L, Batia LM, Beattie K, Katibah GE, McClain SP, Pellegrino M, Estandian DM, Bautista DM. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell. 2013 Oct 10;155(2):285-95. doi: 10.1016/j.cell.2013.08.057. Epub 2013 Oct 3. PMID: 24094650; PMCID: PMC4041105.

Mikesell AR, Isaeva O, Moehring F, Sadler KE, Menzel AD, Stucky CL. Keratinocyte PIEZO1 modulates cutaneous mechanosensation. Elife. 2022 Sep 2;11:e65987. doi: 10.7554/eLife.65987. PMID: 36053009; PMCID: PMC9512397.

Presenting Author

Andrew Crowther

Poster Authors

Sakeen Kashem

MD, PhD

UCSF

Lead Author

Andrew Crowther

University of California San Francisco

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Itch