By Science Daily (Health) | Created at 2026-10-10 20:08:21 | Updated at 2026-10-10 21:40:54
18 hours ago
Chronic diabetic ulcers are among the most difficult complications facing modern healthcare. More than 131 million people worldwide are affected, and the wounds are associated with roughly $755 billion in healthcare costs each year. They also carry serious risks, including amputation and death, making it increasingly important to understand why they can be so resistant to healing.
Immune cells play a central role in coordinating the body's response to injury. However, previous research has often paid less attention to how different immune cell populations change over time as diabetic wounds progress through different stages of healing. A comprehensive review by Yi Ru and colleagues examines this issue in detail, looking at how a wide range of immune cells behave throughout the wound healing process.
How Immune Cells Shape Diabetic Wound Healing
The review covers monocytes, macrophages, dendritic cells, neutrophils, mast cells, B cells, T cells, and natural killer cells. The researchers focus on where these cells appear during different stages of healing and how diabetes can disrupt their normal behavior.
Monocytes and macrophages receive particular attention. The authors examine how different monocyte populations change over time and assess the debated M1/M2 macrophage polarization model. During normal healing, monocytes move into damaged tissue and develop into macrophages. These macrophages typically shift from pro-inflammatory M1 states toward pro-reparative M2 states, allowing inflammation to subside and tissue repair to move forward.
In diabetic wounds, that transition can break down. Macrophages may remain locked in pro-inflammatory states instead of moving toward repair, prolonging tissue damage and preventing the wound from progressing normally.
Neutrophils and Mast Cells Can Sustain Inflammation
Neutrophils are among the first immune cells to arrive after tissue injury. They help destroy pathogens and trigger the early inflammatory response. In diabetic wounds, however, the formation of neutrophil extracellular traps can become poorly regulated.
This abnormal activity can prolong inflammation and damage tissue through excessive release of proteases and reactive oxygen species.
Mast cells also contribute to healing by releasing histamine, serotonin, and several growth factors. These substances influence blood vessel permeability and help recruit additional cells to the wound. According to the review, mast cell degranulation differs substantially between normal and diabetic wounds, and excessive activation may help maintain chronic inflammation.
Dendritic Cells May Fail to Clear Cellular Debris
Dendritic cells also have an important role in wound healing. Langerhans cells in the epidermis and dendritic cells in the dermis help connect the innate and adaptive branches of the immune system by presenting antigens to other immune cells.
Recent evidence suggests that dendritic cells become less effective at efferocytosis in diabetic wounds. This process normally removes apoptotic cells, but when it is impaired, dead cellular material can accumulate and continue triggering inflammatory signals.
The SLC7A11 transporter appears to be an important regulator of this process. Its reduced activity in diabetes may weaken dendritic cell function and interfere with the resolution of wounds.
T Cells Help Control Inflammation and Repair
T lymphocytes, including regulatory T cells and γδ T cells, also help coordinate healing and regulate inflammation.
Regulatory T cells normally suppress excessive immune activity and encourage production of factors involved in tissue remodeling. In diabetic wounds, both the number and function of these cells can decline, and this reduction is associated with slower healing.
Dendritic epidermal T cells are a specialized population of γδ T cells found in the skin. They produce insulin-like growth factor 1 and other growth factors that help keratinocytes multiply and close wounds. Under diabetic conditions, these cells show lower activation and reduced cytokine production.
B Cells and Natural Killer Cells Also Play a Role
B cells and natural killer cells are less thoroughly studied in wound healing, but emerging evidence suggests that both make meaningful contributions.
B cells can influence healing through antibody production and by affecting macrophage polarization. Natural killer cells help regulate inflammation and the formation of new blood vessels through cytokine production and interactions with other immune cells.
The review points to recent evidence showing that recruitment of B cells can encourage macrophages to adopt M2 states, helping reduce excessive inflammation as healing progresses.
New Treatments Could Reprogram the Immune Response
A deeper understanding of immune behavior in diabetic wounds could open the door to new treatments.
The review highlights advances in therapies designed to directly modify immune activity, including topical anti-cytokine biologics that disrupt persistent inflammatory signaling. Approaches that influence macrophage polarization are especially promising, with several drugs showing an ability to encourage M2 states and speed wound closure.
Mesenchymal stem cell therapies and extracellular vesicles derived from these cells may also provide broad immune-regulating effects. Advanced biomaterials and smart dressings could offer another option by delivering immune-modifying substances directly to the wound.
Other emerging approaches include Janus liposozyme technologies designed to regulate redox balance and immune homeostasis, macrophage-regulating drugs that have shown benefits in randomized clinical trials, and IL-15 superagonists that boost the activity of dendritic epidermal T cells.
Timing May Be Critical for Diabetic Wound Treatment
The researchers emphasize that effective treatment may depend not only on which immune cells are targeted, but also on when they are targeted.
Diabetic wounds pass through inflammatory, proliferative, and remodeling stages, and each phase has a different immune environment. As a result, therapies that are useful at one stage may not have the same effect at another.
Future approaches could include personalized treatment plans based on immune profiling of individual wounds. Researchers are also exploring combination therapies that target several immune cell populations at once, while continuing to investigate unresolved questions about how macrophages should be classified.
The authors argue that a better understanding of how immune cell populations interact over time could lead to more precise and effective treatments for diabetic ulcers, one of the most serious and persistent complications of diabetes.
