Chronic diabetic ulcers are among the most challenging complications facing modern health care. More than 131 million people worldwide are affected and injuries are associated with approximately $755 billion in healthcare costs each year. They also carry serious risks, including amputation and death, making it increasingly important to understand why they may be so resistant to recovery.
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 populations of immune cells change over time as diabetic wounds progress through different stages of healing. A comprehensive study by Yi Ru and colleagues examines this question in detail, examining the behavior of a wide range of immune cells throughout the 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. Researchers are focusing on where these cells appear during different stages of healing and how diabetes can disrupt their normal behavior.
Monocytes and macrophages are the subject of particular attention. The authors examine the evolution of different monocyte populations over time and evaluate the controversial M1/M2 macrophage polarization model. During normal healing, monocytes move into damaged tissues and develop into macrophages. These macrophages typically transition from pro-inflammatory M1 states to pro-reparative M2 states, allowing inflammation to subside and tissue repair to advance.
In diabetic wounds, this transition may be interrupted. Macrophages may become stuck in pro-inflammatory states instead of progressing toward repair, thereby prolonging tissue damage and preventing the wound from progressing normally.
Neutrophils and mast cells can maintain inflammation
Neutrophils are among the first immune cells to appear after tissue injury. They help destroy pathogens and trigger the early inflammatory response. However, in diabetic wounds, the formation of neutrophil extracellular traps may become poorly regulated.
This abnormal activity can prolong inflammation and tissue damage due to 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 the permeability of blood vessels and help recruit additional cells to the wound. According to the review, mast cell degranulation differs significantly between normal and diabetic wounds, and excessive activation may help maintain chronic inflammation.
Dendritic cells may not clear cellular debris
Dendritic cells also play an important role in wound healing. Langerhans cells of the epidermis and dendritic cells of 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 against efferocytosis in diabetic wounds. This process normally eliminates apoptotic cells, but when impaired, dead cellular material can accumulate and continue to trigger 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 wound resolution.
T cells help control inflammation and repair themselves
T cells, 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 the production of factors involved in tissue remodeling. In diabetic wounds, the number and function of these cells may decrease, and this reduction is associated with slower healing.
Epidermal dendritic 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 exhibit lower activation and reduced cytokine production.
B cells and natural killer cells also play a role
B cells and natural killer cells are less extensively studied in wound healing, but emerging evidence suggests that both make significant contributions.
B cells can influence healing through the production of antibodies and by affecting macrophage polarization. Natural killer cells help regulate inflammation and the formation of new blood vessels through the production of cytokines and interactions with other immune cells.
The review highlights recent evidence showing that B cell recruitment can encourage macrophages to adopt M2 states, thereby helping to 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 particularly promising, with several drugs showing the ability to promote M2 states and accelerate wound closure.
Mesenchymal stem cell therapies and extracellular vesicles derived from these cells may also have broad immune regulatory effects. Advanced biomaterials and smart dressings could offer another option by delivering immune-modifying substances directly into the wound.
Other emerging approaches include Janus liposozyme technologies designed to regulate redox balance and immune homeostasis, macrophage regulatory drugs that have shown benefit in randomized clinical trials, and IL-15 superagonists that stimulate epidermal dendritic T cell activity.
Timing May Be Critical in Treating Diabetic Wounds
The researchers point out that the effectiveness of the 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 time 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 targeting multiple immune cell populations at once, while continuing to study 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.
Gn Health
