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Peer-reviewedCC BY-NC-NDCell press blue

Cutaneous nonpeptidergic neurons sense extracellular ATP to augment barrier repair and C. albicans host defense.

  • Tara N Edwards1
  • Chien-Sin Chen1
  • Richard T Cattley2
  • Isha Mehta3
  • Ogechukwu Ezenwa3
  • Shiqun Zhang4
  • Lindsay M McKendrick1
  • Sydney-Lam N Nguyen1
  • Anjelica J Ferguson1
  • Andrew W Liu1
  • Paul Yifan Zhou5
  • Alicia R Mathers1
7 more authors
  • Sarah L Gaffen6
  • Kathryn M Albers7,8
  • H Richard Koerber7,8
  • Brian M Davis7,8
  • William F Hawse2
  • Jishnu Das2,3
  • Daniel H Kaplan1,9
9 affiliations
  1. 1Departments of Dermatology and Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  2. 2Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  3. 3Department of Immunology and Computational Immunogenomics (CIG) Core, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  4. 4Department of Pharmacology, School of Medicine, Tongji University, Shanghai, China.
  5. 5Department of Biology, Georgetown University, Washington, DC 20057, USA.
  6. 6Division of Rheumatology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  7. 7Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  8. 8Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  9. 9Lead contact.
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Abstract

Cutaneous pain-sensing nociceptive neurons can directly recognize pathogen invasion and modulate the resulting host immune response. Neuronal recognition of C. albicans cell wall components is necessary and sufficient for optimal protective local type-17 immune responses. We now report a parallel neuroimmune pathway in which extracellular ATP (eATP) released from C. albicans and keratinocytes activates nonpeptidergic neurons, including Mas-related G protein-coupled receptor D (Mrgprd)-expressing NP1 neurons, through the P2X3 ATP receptor. Ablation of NP1 neurons or P2rx3 increased C. albicans colony-forming units (CFUs), but the induction of type-17 responses was unaffected. Rather, transcriptomic analysis revealed an alteration in genes and pathways associated with barrier repair. P2rx3-/- mice showed increased wound size and transepidermal water loss associated with a delay in barrier repair following C. albicans infection or abrasion. These data identify a neuroimmune circuit where nonpeptidergic neurons sense epidermal damage or infection through eATP and P2X3, resulting in augmented barrier repair and thus host defense.

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Cite

BibTeXRIS
BibTeX
@article{edwards2026cutaneous,
  title = {{Cutaneous nonpeptidergic neurons sense extracellular ATP to augment barrier repair and C. albicans host defense.}},
  author = {Tara N Edwards and Chien-Sin Chen and Richard T Cattley and Isha Mehta and Ogechukwu Ezenwa and Shiqun Zhang and Lindsay M McKendrick and Sydney-Lam N Nguyen and Anjelica J Ferguson and Andrew W Liu and Paul Yifan Zhou and Alicia R Mathers and Sarah L Gaffen and Kathryn M Albers and H Richard Koerber and Brian M Davis and William F Hawse and Jishnu Das and Daniel H Kaplan},
  journal = {Cell press blue},
  year = {2026},
  month = aug,
  doi = {10.1016/j.cpblue.2026.100103},
  url = {https://europepmc.org/article/MED/43011974},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Cutaneous nonpeptidergic neurons sense extracellular ATP to augment barrier repair and C. albicans host defense.
AU  - Tara N Edwards
AU  - Chien-Sin Chen
AU  - Richard T Cattley
AU  - Isha Mehta
AU  - Ogechukwu Ezenwa
AU  - Shiqun Zhang
AU  - Lindsay M McKendrick
AU  - Sydney-Lam N Nguyen
AU  - Anjelica J Ferguson
AU  - Andrew W Liu
AU  - Paul Yifan Zhou
AU  - Alicia R Mathers
AU  - Sarah L Gaffen
AU  - Kathryn M Albers
AU  - H Richard Koerber
AU  - Brian M Davis
AU  - William F Hawse
AU  - Jishnu Das
AU  - Daniel H Kaplan
PY  - 2026
DA  - 2026/08/20
JO  - Cell press blue
DO  - 10.1016/j.cpblue.2026.100103
UR  - https://europepmc.org/article/MED/43011974
AB  - Cutaneous pain-sensing nociceptive neurons can directly recognize pathogen invasion and modulate the resulting host immune response. Neuronal recognition of C. albicans cell wall components is necessary and sufficient for optimal protective local type-17 immune responses. We now report a parallel neuroimmune pathway in which extracellular ATP (eATP) released from C. albicans and keratinocytes activates nonpeptidergic neurons, including Mas-related G protein-coupled receptor D (Mrgprd)-expressing NP1 neurons, through the P2X3 ATP receptor. Ablation of NP1 neurons or P2rx3 increased C. albicans colony-forming units (CFUs), but the induction of type-17 responses was unaffected. Rather, transcriptomic analysis revealed an alteration in genes and pathways associated with barrier repair. P2rx3-/- mice showed increased wound size and transepidermal water loss associated with a delay in barrier repair following C. albicans infection or abrasion. These data identify a neuroimmune circuit where nonpeptidergic neurons sense epidermal damage or infection through eATP and P2X3, resulting in augmented barrier repair and thus host defense.
SN  - 3051-3839
ER  -