Keratinocytes contribute to normal cold and heat sensation

  1. Katelyn E Sadler
  2. Francie Moehring
  3. Cheryl L Stucky  Is a corresponding author
  1. Medical College of Wisconsin, United States

Abstract

Keratinocytes are the most abundant cell type in the epidermis, the most superficial layer of skin. Historically, epidermal-innervating sensory neurons were thought to be the exclusive detectors and transmitters of environmental stimuli. However, recent work from our lab (Moehring et al., 2018) and others (Baumbauer et al., 2015) has demonstrated that keratinocytes are also critical for normal mechanotransduction and mechanically-evoked behavioral responses in mice. Here, we asked whether keratinocyte activity is also required for normal cold and heat sensation. Using calcium imaging, we determined that keratinocyte cold activity is conserved across mammalian species and requires the release of intracellular calcium through one or more unknown cold-sensitive proteins. Both epidermal cell optogenetic inhibition and interruption of ATP-P2X4 signaling reduced reflexive behavioral responses to cold and heat stimuli. Based on these data and our previous findings, keratinocyte purinergic signaling is a modality-conserved amplification system that is required for normal somatosensation in vivo.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Katelyn E Sadler

    Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2078-3527
  2. Francie Moehring

    Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0071-5685
  3. Cheryl L Stucky

    Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, United States
    For correspondence
    cstucky@mcw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4966-6594

Funding

National Institutes of Health (NS040538)

  • Cheryl L Stucky

National Institutes of Health (NS070711)

  • Cheryl L Stucky

National Institutes of Health (NS108278)

  • Cheryl L Stucky

National Institutes of Health (NS106789)

  • Katelyn E Sadler

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All protocols were in accordance with National Institutes of Health guidelines and were approved by the Institutional Animal Care and Use Committee at the Medical College of Wisconsin (Milwaukee, WI; protocol #383).

Copyright

© 2020, Sadler et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,146
    views
  • 461
    downloads
  • 67
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

Share this article

https://doi.org/10.7554/eLife.58625

Further reading

    1. Neuroscience
    Kyle M Baumbauer, Jennifer J DeBerry ... Kathryn M Albers
    Research Article Updated

    How thermal, mechanical and chemical stimuli applied to the skin are transduced into signals transmitted by peripheral neurons to the CNS is an area of intense study. Several studies indicate that transduction mechanisms are intrinsic to cutaneous neurons and that epidermal keratinocytes only modulate this transduction. Using mice expressing channelrhodopsin (ChR2) in keratinocytes we show that blue light activation of the epidermis alone can produce action potentials (APs) in multiple types of cutaneous sensory neurons including SA1, A-HTMR, CM, CH, CMC, CMH and CMHC fiber types. In loss of function studies, yellow light stimulation of keratinocytes that express halorhodopsin reduced AP generation in response to naturalistic stimuli. These findings support the idea that intrinsic sensory transduction mechanisms in epidermal keratinocytes can directly elicit AP firing in nociceptive as well as tactile sensory afferents and suggest a significantly expanded role for the epidermis in sensory processing.

    1. Neuroscience
    2. Physics of Living Systems
    Moritz Schloetter, Georg U Maret, Christoph J Kleineidam
    Research Article

    Neurons generate and propagate electrical pulses called action potentials which annihilate on arrival at the axon terminal. We measure the extracellular electric field generated by propagating and annihilating action potentials and find that on annihilation, action potentials expel a local discharge. The discharge at the axon terminal generates an inhomogeneous electric field that immediately influences target neurons and thus provokes ephaptic coupling. Our measurements are quantitatively verified by a powerful analytical model which reveals excitation and inhibition in target neurons, depending on position and morphology of the source-target arrangement. Our model is in full agreement with experimental findings on ephaptic coupling at the well-studied Basket cell-Purkinje cell synapse. It is able to predict ephaptic coupling for any other synaptic geometry as illustrated by a few examples.