# Characterization of interferon kappa as a novel target in cutaneous lupus

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $470,189

## Abstract

PROJECT SUMMARY/ABSTRACT
Cutaneous inflammation is a prevalent and often difficult-to-treat manifestation of systemic lupus erythematosus
(SLE) that is driven in part by elevated type I IFN signaling that leads to increased myeloid cell recruitment and
activation, increased keratinocyte cell death, repression of regulatory cell responses, and increased chemokine
and cytokine production. The sources of type I IFN production in cutaneous lesions include recruited immune
cells and skin-intrinsic sources of type I IFNs, including keratinocyte production of IFNκ. The mechanisms that
drive and regulate increased keratinocyte production of type I IFNs remain unknown yet are important novel
targets for therapeutic intervention. Our preliminary data support a critical role for mitochondrial-triggered STING
signaling in the upregulation of IFNB and IFNK transcription that is enhanced by type I IFN production of Z-nucleic
acid binding protein 1 (ZBP1). Upregulation of type I IFNs is paralleled by increased expression of type III IFNs
(IFNλ family) in a similar fashion, and their interplay with type I IFNs may lead to inflammatory responses not
targeted by anti-IFNAR treatment approaches. Our preliminary data support UVB-driven IFNλ 1 and 3 expression
in human KCs, with regulation downstream of UV activation in a manner like IFNK and IFNB respectively. The
contributions of IFNλ to type I IFN-driven immune responses remain unknown. Thus, the next 5 years of funding
of this grant will focus on dissecting detailed mechanisms of keratinocyte IFN regulation with a new focus on
mitochondrial upregulation of type I IFNs in keratinocytes, the interplay with type III IFNs, and the study of type
I IFN signaling blockade in SLE patient skin. Our overall hypothesis is that in the majority of SLE patients, chronic
over-production of IFNκ is perpetuated through an IFN-primed Z-DNA binding protein (ZBP1) and mitochondrial
oxidation-dependent activation of STING that requires IFNβ and potentially type III IFNs to sustain and or amplify
inflammatory signaling. Patients refractory to IFN blockade may have activation of additional signals downstream
of mitochondrial stress that drive persistent inflammation. Three aims are proposed: Aim 1: Dissect the role of
the mitochondria in keratinocyte IFN regulation. Aim 2: Determine the SLE-relevant interactions between
type I and type III IFNs in keratinocytes. Aim 3: Determine how type I IFN blockade changes inflammatory
phenotypes in SLE skin and determine the critical pathways that remain in refractory disease. When
completed this project will identify novel ways of targeting skewed interferon production and uncover novel, non-
type I IFN pathways that contribute to ongoing disease.

## Key facts

- **NIH application ID:** 10820322
- **Project number:** 2R01AR071384-07
- **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:** 2024
- **Award amount:** $470,189
- **Award type:** 2
- **Project period:** 2017-09-21 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820322

## Citation

> US National Institutes of Health, RePORTER application 10820322, Characterization of interferon kappa as a novel target in cutaneous lupus (2R01AR071384-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10820322. Licensed CC0.

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