Iron and iron-dependent reactive oxygen species in the regulation of macrophages and fibroblasts in non-healing chronic wounds

Chronic wounds pose a stern challenge to health care systems with growing incidence especially in the aged population. In the presence of increased iron concentrations, recruitment of monocytes from the circulation and activation towards ROS and RNS releasing M1 macrophages together with the persistence of senescent fibroblasts at the wound site are significantly enhanced. This unrestrained activation of pro-inflammatory macrophages and senescent fibroblasts has increasingly been acknowledged as main driver causing non-healing wounds. In a metaphor, macrophages act like stage directors of wound healing, resident fibroblasts constitute main actors and increased iron concentrations are decisive parts of the libretto, and – if dysregulated – are responsible for the development of non-healing wounds. This review will focus on recent cellular and molecular findings from chronic venous leg ulcers and diabetic non-healing wounds both constituting the most common pathologies often resulting in limb amputations of patients. This not only causes tremendous suffering and loss of life quality, but is also associated with an increase in mortality and a major socio-economic burden. Despite recent advances, the underlying molecular mechanisms are not completely understood. Overwhelming evidence shows that reactive oxygen species and the transition metal and trace element iron at pathological concentrations are crucially involved in a complex interplay between cells of different histogenetic origin and their extracellular niche environment. This interplay depends on a variety of cellular, non-cellular biochemical and cell biological mechanisms. Here, we will highlight recent progress in the field of iron-dependent regulation of macrophages and fibroblasts and related pathologies linked to non-healing chronic wounds. [Display omitted] •Temporal and spatial interactions between macrophages and fibroblasts with balanced ROS release ensure tissue repair.•Persistence of pro-inflammatory M1 macrophages and senescent fibroblasts contributes to the hostile wound microenvironment.•Iron-dependent oxidative stress affects distinct cells and initiates and maintains the pathology of non-healing wounds.