Discovery Pinpoints Deregulated Immune Cell Recruitment that May Underlie Non-Healing Diabetic Foot Ulcers

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Investigators at the University of Miami Miller School of Medicine, in collaboration with National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) researchers, demonstrate in a new study that the immune response may not be robust enough to heal chronic diabetic foot ulcers (DFUs).

Immune response during normal acute wound healing, showing immune cells in blue and turquoise and skin wound in red.

This novel finding stands in contrast to earlier theories that pointed to a chronic inflammation stalling the wound healing process. The new results were reported in the prestigious journal Nature Communications on September 16.

Similarities and differences in how the immune system responds to wounds in different types of wounds, such as those of normal skin, oral mucosa and DFUs, could be critical in understanding why people with diabetes mellitus can develop DFUs that resist healing over time.

The Laboratories of Marjana Tomic-Canic, Ph.D., director of the Wound Healing and Regenerative Medicine Research Program at the Miller School, and Dr. Maria Morasso, chief of the Laboratory of Skin Biology at NIH, analyzed biopsies from these different human wounds. The researchers studied oral mucosa wounds because they heal rapidly without leaving a scar. They used next-generation sequencing to compare cellular signals that orchestrate the complex interplay of neutrophils, macrophages and other immune system components called to action to heal a wound.

Immune cells not working

The researchers demonstrated that when it comes to DFUs, most of these immune cells either are not showing up for work or are doing an inadequate job.

Neutrophils and macrophages, for example, were each present in lower numbers in the DFUs biopsied from patients compared to skin and oral wounds. Both cell types play essential roles: neutrophils kill invading microbes and help eliminate infection. They also signal macrophages to a wound to help with healing. The research shows macrophages get recruited but often remain inactivated.

In other published research, Sawaya, Stone et al also implicated factors that regulate this immune response in the impaired wound healing process. In DFUs, for example, activity of a regulator called FOXM1 that promotes cell proliferation and viability of inflammatory cells is likewise suppressed.

Inflammation signals provide a clue

“We found that signals, such as FOXM1, that control inflammation provide a key to non-healing of diabetic foot ulcers,” Dr. Tomic-Canic said. “These dysregulated signals preclude recruitment of inflammatory cells to the site of the injury that prevents progression of healing in patients.”

These findings could be particularly important for developing treatments for DFUs in the future.

“Importantly, when we apply an inhibitor to FOXM1 we can promote healing and speed wound closure,” she added.

In an effort to internally validate their findings, the researchers found the same dysregulated immune process leads to non-healing ulcers in mouse diabetic wound models.

Dr. Tomic-Canic credits collaboration among Miller School faculty, including Rivka C. Stone, M.D., Ph.D., (co-first author), Irena Pastar, Ph.D., and Ivan Jozic, Ph.D., each affiliated with the Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, as well as Natasa Strbo, M.D., Ph.D., from the Department of Microbiology & Immunology. Also critical to the success of the research were NIH/NIAMS Laboratory of Skin Biology co-investigators Maria Morasso, Ph.D. (co-corresponding author), Andrew Sawaya, Ph.D. (former graduate of UM’s Molecular Cell Pharmacology Graduate Program and study’s co-first author), Kowser Hasneen, M.Sc., Spencer Mehdizadeh, B.S., and Stephen Brooks, Ph.D., from the NIAMS Biodata Mining and Discovery Section.

Collaboration tackles complex problems

“This proves once again how team efforts that include patients, clinicians and scientists from multiple institutions can tackle such a complex clinical problem and provide solutions for new therapeutics,” Dr. Tomic-Canic said.

In terms of next steps, “there are two directions from here,” Dr. Tomic-Canic said. “One is to use this research approach as a platform to understand more about the pathophysiology of this devastating disease. In doing so, we can simultaneously uncover multiple targets and processes that can be targeted for therapy.”

The second future aim is to bring effective therapy to patients.

The study was supported by an NIH Bench-to-Bedside award from the NIH Office of Clinical Research, the Diabetic Foot Consortium of the National Institutes of Diabetes, Digestive and Kidney Diseases, and grants from the Intramural Research Program of NIAMS.

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