# Characterization of Interferon Kappa as a Novel Target in Cutaneous Lupus

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $345,314

## Abstract

ABSTRACT
Type I interferons (IFNs) are increased in cutaneous lupus erythematosus (CLE) lesions and contribute to
disease pathogenesis, yet skin-intrinsic sources of type I IFN have not been explored. Keratinocytes are the
primary source of IFN kappa (κ), a type I IFN that is a genetic risk factor for cutaneous lupus, significantly
upregulated in CLE skin lesions, and is produced more robustly from systemic lupus erythematosus (SLE) vs.
control keratinocytes. Importantly, neutralization of IFNκ signaling eliminates hyper-inflammatory responses to
ultraviolet light and toll-like receptor agonists in SLE keratinocytes. Thus, IFNκ primes the abundant cutaneous
inflammatory response in SLE. It is consequently critical to understand the regulation of IFNκ and its role in
regulation of inflammatory cytokine production and recruitment of cellular infiltrates as IFNκ may prove to be a
specific target for treatment or prevention of cutaneous lesions, and its specific inhibition may consequently
avoid side effects from systemic blockade of other type I IFNs. The overall objective for this project is to define
the mechanisms and consequences of aberrant regulation of IFNκ in SLE skin. It is hypothesized that hyper-
production of IFNκ is a mechanism by which SLE keratinocytes are primed to overproduce inflammatory
cytokines and chemokines and consequently increase inflammatory responses and that IFNκ will thus serve as
a specific and viable target for prevention or treatment of SLE-associated skin lesions. The proposal will
address this hypothesis through investigation of the following: Aim 1: Identify the mechanisms underlying
increased production of IFNκ in lupus keratinocytes. Regulation of IFNκ by IFNs, STING signaling and
methylation changes will be explored in control and SLE (including consideration of CLE subtypes)
keratinocytes. Aim 2: Identify the mechanisms by which keratinocyte-produced IFNκ promotes
inflammatory responses. Effects of IFNκ on keratinocyte IFN production, monocyte, dendritic cell, and
plasmacytoid dendritic cell recruitment and activation in vitro and in vivo will be explored. Aim 3: Identify the
in vivo impact of IFNκ overexpression on cutaneous inflammation and systemic autoimmunity.
Characterization of cutaneous and systemic autoimmunity and response to cutaneous inflammatory stimuli will
be completed in a novel mouse that overexpresses IFNκ in the epidermis. Completion of this work will support
a paradigm shift in which keratinocyte-derived IFNκ is recognized as an important step for priming and
persistence of a hyper-inflammatory response in SLE skin and is identified as a specific target for future
treatment and prevention of SLE-associated skin lesions.

## Key facts

- **NIH application ID:** 10004499
- **Project number:** 5R01AR071384-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Joanne Michelle Kahlenberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,314
- **Award type:** 5
- **Project period:** 2017-09-21 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004499

## Citation

> US National Institutes of Health, RePORTER application 10004499, Characterization of Interferon Kappa as a Novel Target in Cutaneous Lupus (5R01AR071384-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10004499. Licensed CC0.

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