Macrophage Differentiation in Normal and Accelerated Wound Healing

Abstract

Chronic wounds pose considerable public health challenges and burden. Wound healing is known to require the participation of macrophages, but mechanisms remain unclear. The M1 phenotype macrophages have a known scavenger function, but they also play multiple roles in tissue repair and regeneration when they transition to an M2 phenotype. Macrophage precursors (mononuclear cells/monocytes) follow the influx of PMN neutrophils into a wound during the natural wound-healing process, to become the major cells in the wound. Natural wound-healing process is a four-phase progression consisting of hemostasis, inflammation, proliferation, and remodeling. A lag phase of 3–6 days precedes the remodeling phase, which is characterized by fibroblast activation and finally collagen production. This normal wound-healing process can be accelerated by the intracellular delivery of ATP to wound tissue. This novel ATP-mediated acceleration arises due to an alternative activation of the M1 to M2 transition (macrophage polarization), a central and critical feature of the wound-healing process. This response is also characterized by an early increased release of pro-inflammatory cytokines (TNF, IL-1 beta, IL-6), a chemokine (MCP-1), an activation of purinergic receptors (a family of plasma membrane receptors found in almost all mammalian cells), and an increased production of platelets and platelet microparticles. These factors trigger a massive influx of macrophages, as well as in situ proliferation of the resident macrophages and increased synthesis of VEGFs. These responses are followed, in turn, by rapid neovascularization and collagen production by the macrophages, resulting in wound covering with granulation tissue within 24 h.

Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

“…The numbers of patients with chronic wounds, such as diabetic, venous and pressure ulcers, are rising annually and globally, resulting in a substantial economic burden in developed countries [7]. Furthermore, wounds in aged or diabetic patients are refractory to treatments and can become chronic [26]. The most postulated pathogenic mechanism for chronic wounds is that the switch from a proinflammatory M1 macrophage to an anti-inflammatory M2 phenotype is dysregulated due to impaired efferocytosis of apoptotic neutrophils at the wound site [6,7,19].…”

Unusual Bone Lesions with Osteonecrosis Mimicking Bone Metastasis of Squamous Cell Carcinoma in Recessive Dystrophic Epidermolysis Bullosa

“…Most of these factors could be produced in the tumour environment (12). In addition, these factors could also be produced in chronic wounds and scars, and fibroblasts obtained from patients with RDEB manifest increased amounts of MMPs and TGF-β (13)(14)(15). Therefore, although the precise mechanism underlying the unusual bone lesions in the current case remains unclear, we speculate that various humoral factors carried by the feeder arteries from the primary cSCC lesion and surrounding the multiple chronic wounds and scars might be intricately involved in the development of osteonecrosis.…”

Deficient Skeletal Muscle Regeneration after Injury Induced by a Clostridium perfringens Strain Associated with Gas Gangrene

“…However, it is likely that the early disruption of the microvascular network in the infected muscle affects the process of regeneration, since key steps in muscle regeneration require that an intact blood supply is present within the first hours after myonecrosis. Muscle healing is critically affected by ischemia associated with a deficient blood supply (17). The most critical consequence of ischemia is a decrease in the cellular energy supply (17), as energy is required for every aspect of the wound-healing process, such as protein synthesis, cell migration and proliferation, membrane transport, and growth factor production (17).…”

“…Muscle healing is critically affected by ischemia associated with a deficient blood supply (17). The most critical consequence of ischemia is a decrease in the cellular energy supply (17), as energy is required for every aspect of the wound-healing process, such as protein synthesis, cell migration and proliferation, membrane transport, and growth factor production (17). Under these circumstances, the observed revascularization process may have occurred at a time when the muscle regenerative process had already been impaired.…”