# Immune Functions of Cutaneous Nociceptors

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $506,064

## Abstract

Project Summary
The skin functions as a protective physical barrier as well as an immunologic organ that protects the
host from pathogens but is also subject to autoinflammatory disease. Immunity in the skin involves the
development of inflammatory cytokine cascades between different cell types that both promote host
defense but are pathogenic in disease. For example, IL-23 from dermal dendritic cells drives
production of IL-17 from T cells resulting inn host defense against extracellular pathogens but this
cascade is also pathogenic in diseases such as psoriasis vulgaris and hidradenitis suppurative. A
similar cascade involving IL-4 and IL-13 has been described for defense against parasites and atopic
dermatitis. Recently, it has become appreciated that TRPV1-expressing cutaneous neurons play an
obligate role in cutaneous inflammation across a wide variety of contexts, but the exact mechanism
remains unknown. In the past cycle of this grant we explored whether activation of TRPV1-expressing
neurons in the absence of any tissue damage could trigger inflammation. Using optogenetics, we
found that multiple rounds of activation of TRPV1-expressing neurons with laser light was sufficient to
trigger Type-17 inflammation which was dependent on the neuropeptide CGRP released from sensory
nerve terminals and dermal dendritic cells. Host defense against epicutaneous C. albicans and S.
aureus infection was augmented, and both the Type-17 inflammation and host defense extended
beyond the site of stimulation through a nerve reflex arc providing regional anticipatory immunity. The
temporal precision of optogenetic stimulation allows us to interrogate the early stages of TRPV1-
mediated neuroinflammation. In this proposal we seek to test the hypothesis that neuroinflammation
triggered by TRPV1-expressing neurons initially activates mast cells resulting in clustering of immune
cells which then allows for CGRP-dependent production of IL-23 from dermal dendritic cells. We will
also test whether TRPV1-expressing neurons not only trigger inflammation but also provide a positive
feed-back loop that is required to maintain ongoing inflammation. Finally, we examine whether
stimulation of TRPV1-expressing neurons affect adaptive immunity and is sufficient to trigger Th17
differentiation and reactivation of cutaneous resident memory Th17. Our expectation is that by more
fully delineating neuroinflammatory pathways, we will obtain basic insight into the development of
innate immune responses and allow for potential therapeutic intervention. Moreover, modulation of
adaptive immunity by TRPV1-expressing neurons would link neuroinflammation with flares in
established Type-17 autoimmune diseases such as psoriasis as well as potentially with the
development of autoimmunity associated with chronic pain

## Key facts

- **NIH application ID:** 10534472
- **Project number:** 2R01AR071720-06A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Daniel H Kaplan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $506,064
- **Award type:** 2
- **Project period:** 2017-03-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10534472

## Citation

> US National Institutes of Health, RePORTER application 10534472, Immune Functions of Cutaneous Nociceptors (2R01AR071720-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10534472. Licensed CC0.

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