Chronic diabetic ulcers represent one of the most challenging complications in modern healthcare, affecting over 131 million people worldwide and generating approximately $755 billion in annual healthcare costs. These wounds are characterized by high amputation and mortality rates, creating an urgent need for deeper understanding of their pathophysiology. Immune cells serve as indispensable orchestrators of wound healing, yet existing literature often overlooks the temporal heterogeneity of immune cell subsets in diabetic ulcers. A comprehensive review by Yi Ru and colleagues addresses this critical gap by systematically examining the roles and characteristics of diverse immune cell populations throughout different stages of diabetic wound healing.
The review encompasses a broad spectrum of immune cells including monocytes, macrophages, dendritic cells, neutrophils, mast cells, B cells, T cells, and natural killer cells, with particular emphasis on their distribution patterns and dysregulation across the healing timeline. Monocytes and macrophages receive special attention, with the authors highlighting dynamic transitions between monocyte subsets and offering systematic evaluation of the controversial M1/M2 macrophage polarization paradigm. In normal wound healing, monocytes recruited to wound sites differentiate into macrophages that transition from pro-inflammatory M1 phenotypes to pro-reparative M2 phenotypes, a shift essential for resolution of inflammation and progression to tissue repair. However, in diabetic wounds, this transition becomes impaired, with macrophages remaining trapped in pro-inflammatory states that perpetuate tissue damage rather than repair.
Neutrophils, as the first responders to tissue injury, play crucial roles in pathogen clearance and inflammatory initiation. In diabetic wounds, neutrophil extracellular trap formation becomes dysregulated, contributing to sustained inflammation and tissue damage through excessive release of proteases and reactive oxygen species. Mast cells contribute to wound healing through release of histamine, serotonin, and various growth factors that modulate vascular permeability and cellular recruitment. The review notes that mast cell degranulation patterns differ significantly between normal and diabetic wounds, with excessive activation contributing to chronic inflammatory states.
Dendritic cells, particularly Langerhans cells in the epidermis and dermal dendritic cells, function as critical antigen-presenting cells that bridge innate and adaptive immunity. Recent evidence indicates that dendritic cell efferocytosis—the clearance of apoptotic cells—becomes impaired in diabetic wounds, leading to accumulation of cellular debris that perpetuates inflammatory signaling. The SLC7A11 transporter emerges as a key regulator of this process, with its downregulation in diabetes compromising dendritic cell function and wound resolution.
T lymphocytes, including regulatory T cells and γδ T cells, contribute to immune modulation and tissue repair. Regulatory T cells facilitate wound healing through suppression of excessive inflammation and promotion of tissue remodeling factors. In diabetic wounds, reduced regulatory T cell numbers and function correlate with delayed healing. Dendritic epidermal T cells, a specialized γδ T cell population in skin, produce insulin-like growth factor-1 and other growth factors that promote keratinocyte proliferation and wound closure. These cells show reduced activation and cytokine production in diabetic conditions.
B cells and natural killer cells represent less characterized but important contributors to wound healing. B cells influence healing through antibody production and modulation of macrophage polarization, while natural killer cells regulate inflammation and angiogenesis through cytokine production and interactions with other immune populations. The review highlights recent evidence that B cell recruitment can promote M2 macrophage polarization, thereby inhibiting excessive inflammation during wound resolution.
The therapeutic implications of immune cell biology in diabetic wounds are substantial. The review highlights advances in immune cell-targeted modulation, including topical anti-cytokine biologics that interrupt sustained inflammatory signaling. Strategies targeting macrophage polarization show particular promise, with various pharmacological agents demonstrating ability to promote M2 phenotype acquisition and accelerate wound closure. Mesenchymal stem cell therapies and their extracellular vesicles offer multimodal immunomodulatory effects, while advanced biomaterials and smart dressings provide localized delivery of immune-modulating factors.
Emerging therapeutic approaches include Janus liposozyme technologies that modulate redox and immune homeostasis, macrophage-regulating drugs that have shown efficacy in randomized clinical trials, and IL-15 superagonists that enhance dendritic epidermal T cell function. The review emphasizes that successful diabetic wound management requires temporal specificity—interventions must account for the distinct immune microenvironments present during inflammatory, proliferative, and remodeling phases.
Future directions highlighted include personalized approaches based on immune profiling of individual wounds, combination therapies targeting multiple immune cell types simultaneously, and resolution of persistent controversies regarding macrophage classification systems. The authors advocate for continued research into the dynamic interplay between immune cell populations and their specific temporal roles in wound healing, suggesting that such understanding will enable development of more effective, targeted interventions for this debilitating complication of diabetes.
DOI
10.1007/s11684-025-1190-y