ABSTRACT
Macrophages are important for effective iron recycling and erythropoiesis, but they also play a crucial role in wound healing, orchestrating tissue repair. Recently, we demonstrated a significant accumulation of iron in healing wounds and a requirement of iron for effective repair. Herein, we sought to determine the influence of iron on macrophage function in the context of wound healing. Interestingly, wound macrophages extensively sequestered iron throughout healing, associated with a prohealing M2 phenotype. In delayed healing diabetic mouse wounds, both macrophage polarization and iron sequestration were impaired. In vitro studies revealed that iron promotes differentiation, while skewing macrophages toward a hypersecretory M2-like polarization state. These macrophages produced high levels of chemokine (C-C motif) ligands 17 and 22, promoting wound reepithelialization and extracellular matrix deposition in a human ex vivo wound healing model. Together, these findings reveal a novel, unappreciated role for iron in modulating macrophage behavior to promote subsequent wound repair. These findings support therapeutic evaluation of iron use to promote wound healing in the clinic.
Subject(s)
Chemokine CCL17/physiology , Chemokine CCL22/physiology , Iron/pharmacology , Macrophages/drug effects , Skin/metabolism , Wound Healing/drug effects , Animals , Cell Differentiation/drug effects , Cell Polarity/drug effects , Cells, Cultured , Chemokine CCL17/metabolism , Chemokine CCL22/metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Disease Models, Animal , Female , Humans , Iron/metabolism , Macrophage Activation/drug effects , Macrophages/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Leptin/genetics , Skin/injuries , THP-1 CellsABSTRACT
Iron is crucial for maintaining normal bodily function with well-documented roles in erythropoiesis, hemostasis, and inflammation. Despite this, little is known about the temporal regulation of iron during wound healing, or how iron contributes to wound biology and pathology. In this study, we profiled tissue iron levels across a healing time-course, identifying iron accumulation during late-stage repair. Diabetic murine wounds displayed significantly reduced iron levels, delayed extracellular matrix deposition, and dysregulation of iron gene expression. In vitro studies revealed important cellular roles for iron, promoting both the deposition and remodeling of extracellular proteins. Functional studies identified oxidative stress-dependent upregulation of the iron-converting metalloreductase, STEAP3, as a key mediator of extracellular matrix production. Taken together, these data reveal a mechanistic role for iron in facilitating the remodeling stage of wound healing. Indeed, targeting tissue iron could be a promising future strategy to tackle the development and progression of chronic wounds.
Subject(s)
Cell Cycle Proteins/metabolism , Diabetes Complications/metabolism , Extracellular Matrix/metabolism , Iron/metabolism , Oxidoreductases/metabolism , Skin/metabolism , Wounds and Injuries/metabolism , Animals , Cell Cycle Proteins/genetics , Cells, Cultured , Disease Models, Animal , Female , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxidative Stress , Oxidoreductases/genetics , RNA, Small Interfering/genetics , Receptors, Leptin/genetics , Skin/pathology , Wound HealingABSTRACT
Cellular senescence can be broadly defined as a stable, but essentially irreversible, loss of proliferative capacity. Historically, senescence has been described as a negative outcome of advanced cellular age. It is now clear, however, that senescence represents a dynamic autonomous stress response, integral to long-term tumor suppression. Transient induction of a senescent phenotype has actually been suggested to promote regeneration in both liver and skin. Here, we explored the role of senescence in pathological aged and diabetic murine wound healing. Aged and diabetic wounds had greater numbers of senescent cells, and diabetic macrophages maintained altered retention of polarization and produced a CXCR2-enriched senescence-associated secretory phenotype (i.e., SASP). Of translational relevance, targeted expression of CXCR2 in primary human dermal fibroblasts led to paracrine induction of nuclear p21. Furthermore, a selective agonist to CXCR2 was able to reverse delayed healing in diabetic mice and accelerate ex vivo human skin wound healing. Collectively, these data suggest a hitherto unappreciated role for CXCR2 in mediating cellular senescence in pathological wound repair.
