September 29, 2020

Poor immune response impairs diabetic wound healing

At a Glance

  • Researchers found that diabetic foot ulcers don’t recruit the immune cells necessary for normal wound healing.
  • The team also identified factors that contribute to this impaired immune response, pointing to potential targets for future therapies.
Doctor bandaging a foot wound Symptoms of diabetes include sores that don’t heal properly. These can lead to diabetic foot ulcers.MangTeng / iStock / Getty Images Plus

Diabetes occurs when your blood glucose, also called blood sugar, is too high. Over time, having too much sugar in your blood can cause health problems, such as heart disease, nerve damage, eye problems, and kidney disease.

Diabetes can also reduce the ability of the skin to heal itself. Even small cuts on the feet can develop into diabetic foot ulcers—chronic, non-healing wounds that are vulnerable to infection. Diabetic foot ulcers are a major cause of lower limb amputations, disability, and death in people with diabetes.

Treatment options for people with diabetic foot ulcers are limited. A better understanding about how the healing process goes awry in these wounds could help researchers design better therapies and diagnostic tools.

A team led by Dr. Maria Morasso from NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and Dr. Marjana Tomic-Canic from the University of Miami looked closely at the inflammatory response in diabetic foot ulcers. Inflammation is caused by the immune system’s reaction to injury or infection. It is a necessary part of the healing process, but if not properly controlled can prevent wounds from healing.

The researchers took tissue samples from the edge of diabetic foot ulcers in 13 people. They used multiple methods to compare these with samples from normally healing small wounds in the mouth and skin of people without diabetes. The mouth wounds provided samples of tissue known to heal very quickly with little or no scarring. The study results were published on September 16, 2020, in Nature Communications.

Neutrophils in acute human skin wound Neutrophils (teal) gather at the site of a human skin wound at day three to promote an inflammatory response during healing. Dr. Andrew Sawaya, NIAMS Laboratory of Skin Biology

Analysis of wounds a few days after injury showed that some gene activity patterns were similar among healthy oral and skin wounds and diabetic foot wounds. However, many processes associated with inflammation and healing were suppressed in the diabetic foot ulcers.

The team found that several genes that help promote tissue repair were highly active in healthy mouth and skin wounds but suppressed in diabetic foot wounds. Two of these genes, FOXM1 and STAT3, are involved in recruiting immune cells necessary for healthy inflammation and wound healing.

Immune cell activity in diabetic foot ulcers differed from that in healthy mouth and skin wounds. Recruitment of neutrophils and macrophages to the injury site, which is necessary for wound healing, was suppressed in the diabetic foot ulcers. Other immune cells that reflect a stalled healing process were more likely to be found in the foot ulcers.

The team next directly tested the role of the FOXM1 protein in wound healing in diabetic mouse models. They applied a compound that blocks FOXM1 to skin wounds. Mice given the compound showed substantially delayed wound healing, similar to people with diabetic foot ulcers. The compound also significantly decreased the number of neutrophils and macrophages in the diabetic wounds.

“Though diabetic foot ulcers are a complex disease with likely many contributing factors, loss of FOXM1 appears to play a role in delayed healing,” Morasso says. “Modulating its function in chronic, non-healing wounds may be a potential therapeutic strategy to restart the stalled healing process.”

—by Sharon Reynolds

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References: Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing. Sawaya AP, Stone RC, Brooks SR, Pastar I, Jozic I, Hasneen K, O'Neill K, Mehdizadeh S, Head CR, Strbo N, Morasso MI, Tomic-Canic M. Nat Commun. 2020 Sep 16;11(1):4678. doi: 10.1038/s41467-020-18276-0. PMID: 32938916.

Funding: NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Nursing Research (NINR), and Office of Clinical Research; University of Miami.