# Nociceptors are Sufficient for Cutaneous Inflammation

> **NIH NIH F30** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $51,036

## Abstract

PROJECT SUMMARY
The skin serves a dual function as an immunological barrier and a sensory interface between the body and
environment. Protection against invading pathogens is accomplished by coordinated interactions between
immune cells in the skin whose aberrant activity can provoke pathologic inflammation. Increasing evidence has
demonstrated a unique role of pain sensing fibers, or nociceptors, in cutaneous immune responses. Briefly,
Trpv1+ nociceptors were found to be required for IL-23-dependant production of IL-17 by dermal gamma delta
and CD4 T-cells. Mice deficient in these nociceptors are more susceptible to C. albicans skin infection but have
diminished pathology in an IMQ mouse model of Type-17 psoriasaform inflammation. The requirement of
nociceptors for cutaneous immunity suggests that neuronal activation by itself may be sufficient to affect the
balance between protective host defense and pathologic inflammation. To test the sufficiency of nociceptors for
skin inflammation, we developed an optogenetic murine model which allows for selective activation of
nociceptors with high temporal and spatial precision. We found that activation of Trpv1+ nerves is sufficient for
skin inflammation involving production of IL-23, IL-6, and TNFα and infiltration of IL-17 producing T-cells.
Interestingly, activation of distinct nociceptors expressing MrgprD induces expression of Type-2 but not Type-17
cytokines. Taken together, the sufficiency of nociceptors to modulate cutaneous immunity highlights nociceptors
as a therapeutic target to enhance host defense or limit pathologic inflammation in the skin. We hypothesize that
activation of Trpv1+ nociceptors is sufficient to activate a cascade of events starting with CGRP activation of
cDC2 which in turn release cytokines that induce IL-17 production from T-cells. We anticipate that this Type-17
immune response will provide protection to epicutaneous S. aureus infection. Finally, we hypothesize that
induction of Type-17 immunity is specific for Trpv1+ nociceptors whereas activation of MrgprD-expressing fibers
will be sufficient for Type-2 immune responses. We will address these questions in three specific aims. Aim 1:
Test the hypothesis that Trpv1+ nociceptor activation drives IL-23, IL-6 and TNFα secretion from cDC2.
Trpv1-Ai32(Chr2-YFP) mice will be cutaneously photostimulated. Tissue will be analyzed by flow cytometry and
qPCR for IL-23, IL-6 and TNFα. Finally, a series bone marrow chimeras will be generated allowing for the
depletion of cDC2 to demonstrate functional non-redundancy. Aim 2: Test the hypothesis that Trpv1+
nociceptors are sufficient and required for host-protection against S. aureus infection. Mice with ablation
of Trpv1+ nociceptors or photostimulated Trpv1-Ai32 mice will be epicutaneously infected with S. aureus. CFU
and immune parameters for Type-17 inflammation will be analyzed by flow cytometry. Aim 3: Test the
hypothesis that MrgprD+ nociceptors are sufficient for Type-2 inflam...

## Key facts

- **NIH application ID:** 10259659
- **Project number:** 5F30AI147396-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jonathan Cohen
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2019-11-01 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10259659

## Citation

> US National Institutes of Health, RePORTER application 10259659, Nociceptors are Sufficient for Cutaneous Inflammation (5F30AI147396-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10259659. Licensed CC0.

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