Scientists may have identified a fundamental reason why chronic diabetic ulcers prove so resistant to healing, a complication that affects over 131 million people worldwide and incurs substantial healthcare costs.
A comprehensive review conducted by Yi Ru and colleagues has explored how various immune cell populations behave throughout the wound healing process, specifically focusing on how diabetes can disrupt their normal function and lead to prolonged inflammation and impaired repair.
Chronic diabetic ulcers represent a significant challenge in modern healthcare, associated with an estimated $755 billion in annual healthcare expenditure. Beyond the financial burden, these wounds carry serious risks for patients, including the potential for amputation and, in severe cases, death. Understanding the underlying mechanisms of their resistance to healing is therefore crucial for developing effective treatments.
Previous research in this area has often overlooked the dynamic changes in different immune cell populations as diabetic wounds progress through their healing stages. The new review addresses this gap, offering a detailed examination of how a wide spectrum of immune cells operate and malfunction in diabetic conditions.
The review provides particular focus on monocytes and macrophages. In a normal healing process, monocytes migrate into damaged tissue and differentiate into macrophages. These macrophages typically transition from a pro-inflammatory state, known as M1, to a pro-reparative state, M2. This shift allows inflammation to subside and tissue repair to advance.
However, in diabetic wounds, this crucial transition can break down. Macrophages may become trapped in persistent pro-inflammatory states, failing to move towards repair. This sustained inflammation prolongs tissue damage and obstructs the normal progression of wound healing.
Neutrophils, among the first immune cells to respond to tissue injury, usually help destroy pathogens and initiate the early inflammatory response. The review notes that in diabetic wounds, the formation of neutrophil extracellular traps (NETs) can become poorly regulated. This abnormal activity can perpetuate inflammation and cause further tissue damage through the excessive release of proteases and reactive oxygen species.
Mast cells also contribute to healing by releasing substances such as histamine, serotonin, and various growth factors, which affect blood vessel permeability and aid in recruiting other cells to the wound site. The researchers found that mast cell degranulation differs significantly between normal and diabetic wounds, with excessive activation potentially contributing to chronic inflammation.
Dendritic cells, including Langerhans cells in the epidermis and dendritic cells in the dermis, play a vital role in connecting the innate and adaptive branches of the immune system by presenting antigens. Recent evidence suggests that in diabetic wounds, dendritic cells become less effective at efferocytosis, the process of removing apoptotic (dead) cells. When this process is impaired, dead cellular material can accumulate, continuing to trigger inflammatory signals.
The SLC7A11 transporter is highlighted as an important regulator of this process, with reduced activity in diabetes potentially weakening dendritic cell function and impeding wound resolution.
T lymphocytes, specifically 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 remodelling. In diabetic wounds, both the number and function of these cells can decline, a reduction associated with slower healing.
Dendritic epidermal T cells, a specialised population of γδ T cells found in the skin, produce insulin-like growth factor 1 (IGF-1) and other growth factors essential for keratinocyte multiplication and wound closure. Under diabetic conditions, these cells exhibit lower activation and reduced cytokine production.
While less thoroughly studied in wound healing, emerging evidence suggests that B cells and natural killer (NK) cells also make meaningful contributions. B cells can influence healing through antibody production and by affecting macrophage polarization, with recent findings indicating their recruitment can encourage macrophages to adopt M2 states, thereby reducing excessive inflammation. NK cells contribute to regulating inflammation and the formation of new blood vessels through cytokine production and interactions with other immune cells.
This deeper understanding of immune behaviour in diabetic wounds could open new avenues for treatment. The review highlights advances in therapies designed to directly modify immune activity, such as topical anti-cytokine biologics that disrupt persistent inflammatory signalling. Approaches that influence macrophage polarization are particularly promising, with several drugs demonstrating an ability to promote M2 states and accelerate wound closure.
Mesenchymal stem cell therapies and extracellular vesicles derived from these cells are also being explored for their broad immune-regulating effects. Additionally, advanced biomaterials and smart dressings could offer a means to deliver immune-modifying substances directly to the wound. Other emerging strategies include Janus liposozyme technologies to regulate redox balance and immune homeostasis, macrophage-regulating drugs that have shown benefits in randomized clinical trials, and IL-15 superagonists designed to boost the activity of dendritic epidermal T cells.
The researchers emphasise that the effectiveness of treatment may depend not only on which immune cells are targeted, but also on the timing of intervention. Diabetic wounds progress through distinct inflammatory, proliferative, and remodelling stages, each characterised by a different immune environment. Consequently, therapies that are beneficial at one stage may not have the same effect at another.
Future approaches could involve personalised treatment plans based on immune profiling of individual wounds. Researchers are also exploring combination therapies that target multiple immune cell populations simultaneously, alongside ongoing investigations into unresolved questions surrounding macrophage classification.
The authors conclude that a more comprehensive understanding of how immune cell populations interact over time holds the potential to lead to more precise and effective treatments for diabetic ulcers, addressing one of the most serious and persistent complications associated with diabetes.
