# Role of IFN kappa in psoriasis-mediated diabetes development

> **NIH NIH R00** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $248,999

## Abstract

PROJECT SUMMARY/ABSTRACT
Recent literature has identified that psoriasis, a prevalent chronic inflammatory skin disease, is associated with
an increased risk of type 2 diabetes (T2D). This is important since the combination of psoriasis and T2D worsen
glycemic control to a greater degree, leading to increased secondary complications than either disease alone;
however, the molecular mechanisms that predispose patients with psoriasis to develop T2D are unknown. In
psoriasis, interferon kappa (IFNκ), a type I IFN, is increased in skin lesions and peripheral blood, leading to
systemic inflammation. Our preliminary data identifies that a histone methyltransferase, Mixed lineage leukemia
protein 1 (MLL1), may control IFNκ expression in keratinocytes, and this may be mechanistically driven by
Tyk2/STAT1 signaling. This overexpression of IFNk by keratinocytes is associated with increased inflammatory
macrophages (MΦs) in skin and adipose tissue and hyperglycemia development. To this end, our preliminary
data identify that keratinocyte-derived IFNκ can drive MΦs towards an inflammatory phenotype via a JMJD3-
mediated mechanism. Further, our group has identified that JMJD3, a histone demethylase, is crucial in
regulating inflammatory MΦs in skin and is upregulated in MΦs following IFNκ/JAK1/STAT3 stimulation. This
K99/R00 proposal seeks to test the hypothesis that Tyk2/STAT1 signaling upregulates MLL1 in keratinocytes
and mechanistically underlies IFNκ overexpression in psoriasis. Further, we propose that this increase in IFNκ
by psoriatic keratinocytes drives MΦs towards an inflammatory phenotype in skin and adipose tissue via a
JMJD3-mediated mechanism. These inflammatory adipose tissue macrophages (ATMs) then drive adipocyte
metabolic dysfunction via regulation of PPARγ and GLUT4. To test these hypotheses, We will pursue the
following aims during the K99 phase of this award: AIM 1: Identify the MLL1-mediated mechanism(s) by which
keratinocyte IFNκ expression is regulated in psoriasis tissue, AIM 2: Examine the mechanism(s) by which
keratinocyte-derived IFNκ regulates MΦ phenotype in psoriasis. During this time, the PI will receive research
training in epigenetic techniques, isolating and culturing human keratinocytes, sequence analysis, and isolating
macrophages from adipose tissue. During the independent phase(R00), she will determine the mechanism(s)
by which ATM-derived TNFα dysregulates adipocyte glucose metabolism in psoriasis and determine if IFNκ
inhibition improves glucose metabolism (AIM 3). Training in the proposed techniques during the K99 phase will
afford the PI the necessary skills to run a successful independent research program studying the relationship
between chronic skin inflammation diseases and metabolic dysfunction.

## Key facts

- **NIH application ID:** 11078495
- **Project number:** 4R00DK133828-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Sonya J Wolf-Fortune
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $248,999
- **Award type:** 4N
- **Project period:** 2022-08-10 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11078495

## Citation

> US National Institutes of Health, RePORTER application 11078495, Role of IFN kappa in psoriasis-mediated diabetes development (4R00DK133828-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11078495. Licensed CC0.

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