# The Interferon-beta (IFN-beta)/SETDB2 Epigenetic Axis Regulates Inflammation And Metabolism In Diabetic Wounds

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $486,408

## Abstract

PROJECT SUMMARY/ABSTRACT
Non-healing wounds in patients with Type 2 Diabetes (T2D) are a major cause of morbidity and mortality and
are increasing at an alarming rate. The factors controlling macrophage function and how these cells transition
from an inflammatory to a reparative phenotype in wound tissues are not understood; leaving a large deficit in
our ability to prevent and treat these wounds. Our laboratory is investigating novel epigenetic changes, induced
via post-transitional modifications of histones, as mechanism(s) to regulate the macrophage phenotype during
wound healing. We present data that the cytokine environment established in wounds following injury induces
the expression of specific epigenetic machinery in macrophages that control gene transcription, and hence,
function. Using human cells and our experimental murine model of wound healing, we have identified that
interferon-beta (IFNβ) induces the expression of SETDB2, an epigenetic-based lysine methyltransferase that is
responsible for setting a suppressive histone mark that results in the silencing of inflammatory and metabolic
genes. This sequence of events is beneficial in normal wound healing, allowing for the transition from an
inflammatory to a reparative macrophage phenotype needed to promote healing. We hypothesize that during
the evolution of normal wound healing, IFNβ-mediated induction of SETDB2 in wound macrophages
represses NFKB-mediated inflammatory and metabolic genes resulting in decreased wound
inflammation and enhanced wound repair. We further postulate that this process does not occur in
diabetic wounds where SETDB2 is not induced in wound macrophages, resulting in increased
inflammation and non-healing wounds. This hypothesis will be investigated via the following specific aims:
1) Elucidate the regulation of NFkB-mediated gene expression by SETDB2 in normal and diabetic wound
macrophages; 2) Determine the IFNβ-mediated mechanism(s) that upregulate macrophage-specific SETDB2
expression in normal and diabetic wound tissue; and 3) Establish the role of SETDB2-regulated uric acid on
normal and diabetic wound macrophage phenotypes during healing.

## Key facts

- **NIH application ID:** 10240278
- **Project number:** 5R01HL137919-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Katherine Ann Gallagher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $486,408
- **Award type:** 5
- **Project period:** 2017-08-09 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240278

## Citation

> US National Institutes of Health, RePORTER application 10240278, The Interferon-beta (IFN-beta)/SETDB2 Epigenetic Axis Regulates Inflammation And Metabolism In Diabetic Wounds (5R01HL137919-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10240278. Licensed CC0.

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