Drilling down on the roots of pathologic inflammation and wound healing challenges in diabetic patients

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This year’s James S. T. Yao Resident Research Award winner looks at novel therapeutic target for non-healing diabetic wounds. Kevin D. Mangum, MD, PhD, speaks to VS@VAM about his paper ahead of presenting the work at the 2024 Vascular Annual Meeting (VAM).

Mangum, who is a vascular surgery integrated resident at the University of Michigan in Ann Arbor, was announced as the winner of the James S. T. Yao Resident Research Award by the SVS Foundation for his paper ‘The STAT3-SETDB2 axis dictates NFKB-mediated inflammation in macrophages during wound repair.”

This award is designed to support emerging medical professionals exploring vascular disease biology and innovative translational therapies. It recognizes unpublished, original scientific work in manuscript form that demonstrates publication quality. The recipient will present his research during the William J. von Liebig Forum, which takes place on the morning of Wednesday, June 19, at 8:10 a.m. (West Building, Level 3, Skyline Ballroom).

Kevin D. Mangum

In the prize-winning paper set to be presented at this year’s Chicago gathering, Mangum sought to determine the transcription mechanisms regulating SETDB2 expression and activity in wound macrophages. “This is important given the critical and dynamic role that SETDB2 plays in regulating inflammatory gene transcription in wound repair,” he and colleagues at the University of Michigan write in their manuscript.

Mangum conducted his research under the mentorship of Katherine Gallagher, MD, vice chair of basic and translational science and professor of surgery in the Section of Vascular Surgery at the University of Michigan. Speaking to VS@VAM ahead of his presentation, Mangum outlined the evolution of his work. “Over the past two years in the Gallagher lab my research has expanded from epigenetic regulation of immune cells in the wound bed to transcriptional alterations in vascular smooth muscle cells in the arterial wall,” he explained. “We’ve been able to dissect specific DNA-protein and protein-protein interactions regulating macrophage phenotype in wound repair and have applied a similar approach to identifying central transcription mechanisms regulating other disease processes like atherosclerosis and hypertension, which will be the central focus of my research investigations after residency.”

Focusing on the specifics of the paper, Mangum continued: “In our manuscript, we build on prior research studying the histone methyltransferase, SETDB2, which is expressed in macrophages and functions to repress inflammation. We’ve shown that macrophages from diabetic patients actually have lower amounts of SETDB2, which is one mechanism underlying pathologic inflammation and worse rates of wound healing in this population. My research really delves into the exact upstream transcription factors controlling SETDB2 expression, as well as those transcriptional regulators binding to SETDB2 protein to further modulate macrophage phenotype.”

In their research manuscript, Mangum and colleagues give further details about the investigation. “We identified that SETDB2 functions with NFKB to regulate the pro-inflammatory transcriptional repertoire in macrophages during wound healing by targeting NFKB-dependent gene regions,” they write, continuing: “We also demonstrate that the transcription factor, STAT3, regulates SETDB2 via two pathways. First, in normal wound macrophages, STAT3 increases SETDB2 expression, which decreases inflammation. In contrast, by a separate mechanism, STAT3 also limits SETDB2 activity by physically binding to and preventing it from trafficking to inflammatory genes.” He explains the importance of this, stating: “Our work identifies a completely novel role for a well-known transcription factor, STAT3, in sequestering SETDB2 from NFkB and its associated gene regions. Strikingly, we found STAT3-SETDB2 binding was increased in diabetic macrophages, thereby leading to increased inflammation. This work has larger implications for transcriptional regulation because it identifies previously unknown functions of critical transcription factors in the regulation of downstream gene expression and cell phenotype.”

“By defining a novel STAT3-SETDB-NFKB axis,” they write in their conclusion, “we have identified several potential targets to treat non-healing diabetic wounds in a cell-specific and time-dependent manner.” For example, Mangum and colleagues state that immunomodulators during early wound healing to increase or activate STAT3 in order to increase SETDB2 expression may be useful. In addition, they write that inhibiting STAT3 relatively later in diabetic wound healing “may prove useful to increase SETDB2 localization to active inflammatory gene regions, thereby inhibiting pathologic inflammation and improving tissue repair.”

In terms of what is next for Mangum in the Gallagher lab, the vascular surgery resident commented that he and the team have “several exciting things” in the pipeline. “We’re mapping the specific protein domains mediating the interactions between SETDB2, STAT3 and NFKB in macrophages in hopes of developing a novel small molecular inhibitor of these interactions that can be used to treat diabetic wound healing in a cell-specific manner.”

Mangum’s “ultimate goal” after completing residency, he told VS@VAM, is “to really understand how additional chromatin modifiers like SETDB2 are functioning in other cell types, specifically in vascular smooth muscle cells, to regulate vascular disease.”

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