# The molecular basis of Interleukin-31 driven itch

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $340,826

## Abstract

PROJECT SUMMARY
Chronic itch is a symptom of many many diseases and causes stress, loss of sleep, and a decline in quality of
life. In addition to the psychological damage, constant scratching physically exacerbates skin disease by
enhancing skin inflammation and promoting infection. However, the only specific treatment options are
antihistamines, which mostly are ineffective. Recently, the cytokine IL-31 was identified as a new target for itch.
A newly-completed Phase II clinical trial of an antibody targeting the IL-31 receptor (IL31RA) showed remarkable
efficacy in reducing itch in atopic dermatitis patients. IL-31 has been proposed to act by stimulating a subset of
neurons in the skin that specifically transmits itch signals, and which is characterized in mice by expression of a
protein called MAS-related G protein- coupled receptor A3 (Mrgpra3). However, while we have confirmed that
Il31ra-positive neurons do exist, they do not overlap with Mrgpra3-positive neurons. However, Mrgprs may be
involved indirectly, as we have preliminary evidence that IL-31 induces keratinocytes to release Mrgpr-activating
substances. Thus, we hypothesize that IL-31 induces itch directly by acting on a new, uncharacterized subset of
neurons, and indirectly by inducing keratinocytes to produce Mrgpr- activating pruritogens. We propose three
sets of experiments to test our hypothesis. First, we will evaluate whether IL-31 induces changes in excitability
and/or transcriptional programming in IL31RA-positive neurons. This could lead to long-term, persistent
increases in itch sensation that may even outlast exposure to IL-31. Second, we will determine whether the
substances released by keratinocytes that activate Mrgprs are members of a newly-identified class of Mrgpr
ligands. We also will examine IL-31-induced itch in Mrgpr knockout mice. Third, we will determine the relative
contributions of IL31RA-positive neurons and keratinocytes in IL-31-induced itch by knocking out IL31RA
specifically in neurons or in epithelial cells. These will inform future research directions and may help to select
drug delivery options. The data generated from our proposed experiments will have direct applications in the
clinic, as the first specific anti-pruritic treatment option since antihistamines is an anti-IL31RA antibody. An
understanding of how IL-31 works is essential to interpret future clinical results, to predict who will and will not
benefit from anti-IL31RA therapy, to develop even more specific treatment options, and to identify other diseases
that might be treated by targeting IL-31.

## Key facts

- **NIH application ID:** 9899207
- **Project number:** 5R01AR073279-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Benjamin Dwight-Clyde McNeil
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $340,826
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899207

## Citation

> US National Institutes of Health, RePORTER application 9899207, The molecular basis of Interleukin-31 driven itch (5R01AR073279-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9899207. Licensed CC0.

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