Relevance of macrophages in the wound healing process among individuals afflicted with diabetic foot ulcers

Abstract

In this paper, we provide a commentary on an article focusing on diabetic foot ulcer (DFU) as a dreadful complication of diabetes mellitus. The development of this condition is influenced by factors such as diabetic peripheral neuropathy, lower extremity artery disease, and infection. However, the underlying mechanism remains elusive. Macrophages play a critical role in wound healing processes, suggesting that therapies targeting these cells could potentially improve the management of DFU. A comprehensive understanding of developmental trends of macrophages within the field of DFU may facilitate research advancements and the development of novel treatment strategies.

Core Tip: Macrophages play a pivotal role in the intricate process of wound healing. Advancements in macrophage research pertaining to diabetic foot ulcer (DFU) hold immense potential for augmenting and expediting the wound healing process associated with DFU.

TO THE EDITOR

Diabetic foot ulcer (DFU) is a prevalent complication of diabetes mellitus, with an estimated lifetime incidence ranging from 19% to 34%[1]. Furthermore, approximately 20% of patients with DFU experience the unfortunate outcome of limb amputation[2]. This not only significantly diminishes their mobility and quality of life but also escalates the risk of mortality by 2.5-fold compared to those without foot ulcers[3]. Consequently, DFU poses a substantial burden on both patients and healthcare system. Treatment for DFU involves management of infection, revascularization, and local wound care. Sometimes, advanced wound treatments are required to accelerate wound healing. Although diabetic peripheral neuropathy, lower extremity artery disease, and infection are well-known etiological factors contributing to the development of DFU, the underlying pathogenesis remains elusive. A profound understanding of the underlying pathogenesis may facilitate the development of advanced wound treatment measures.

Macrophages are innate immune cells that play a crucial role in the process of normal wound healing and tissue regeneration[4]. The complex process of wound healing involves multiple overlapping stages. In the initial stages, macrophages exhibit proinflammatory properties, commonly referred to as M1, and possess antimicrobial activity. As inflammation resolves, macrophages can transit into an anti-inflammatory state known as M2, which may promote the proliferation of stromal and vascular cells and contribute to neovascularization[5]. Dysfunction of macrophages can impair the proper progression of wound healing[6]. In diabetic wounds, there is a delayed influx of macrophages due to temporal lag in chemokine expression, resulting in delayed clearance of debris, microbes, and neutrophils through efferocytosis. Consequently, chronic wounds fail to transit into the proliferation state[7,8].

Because of the diverse activities exhibited by macrophages in wound healing, therapeutic strategies targeting these cells can be categorized into two distinct approaches. In the initial stages, augmenting the quantity or functionality of macrophages may facilitate clearance of pathogen and debris, thereby promoting resolution of chronic inflammation state[4]. Conversely, during later stages, supplementation of activated M2 macrophages or pharmacological interventions aimed at modulating macrophage phenotypic transition could promote release of growth factors and stimulate fibroblast proliferation as well as angiogenesis[9]. Therapeutic interventions targeting macrophages hold significant potential for improving wound healing in DFU.

In the study conducted by Wen et al[10], the authors performed a comprehensive bibliometric analysis of the literature pertaining to macrophage-related DFU. Over the past two decades, there has been a gradual increase in the annual number of publications focusing on macrophages in DFU. China and the United States published the highest number of publications in this field. Notably, Aristitis Veves, an esteemed researcher affiliated with Harvard Medical School, has the most significant publication count in this field. Amongst scientific journals publishing articles related to this topic, “Wound Repair and Regeneration” emerges as having published the largest number of contributions. This study provides valuable insights into developmental trends within this area of research. Furthermore, through the utilization of various visualizations, this article enhances comprehension and facilitates accurate interpretation.

DFU poses a significant and persistent challenge in the management of diabetes mellitus, with macrophages playing a pivotal role in the pathogenesis. Recent bibliometric analysis highlights the escalating research interest in macrophages within the context of DFU, and suggests that therapeutic interventions aimed at modulating these immune cells hold promise for enhancing the wound healing process.