Significance: The immune system plays a central role in orchestrating the tissue healing process. drug delivery methods. Future Directions: Improving our understanding of the molecular pathways through which the immune system controls the wound healing process could facilitate the design of novel regenerative therapies. Additionally, better delivery systems may make current and future therapies more effective. To promote the entry of current regenerative strategies into clinical trials, more evidence on their safety, efficacy, and cost-effectiveness is also needed. indicate differentiation, indicate inhibition K02288 kinase activity assay and K02288 kinase activity assay indicate induction. CXCL, C-X-C chemokine ligand; ECM, extracellular matrix; FGF, fibroblast growth factor; IL, interleukin; MMP, matrix metalloproteinase; NET, neutrophil extracellular trap; ROS, reactive oxygen species; TGF, transforming growth factor; TIMP, tissue inhibitor of matrix metalloproteinase; TNF, tumor necrosis factor. Neutrophils are the first immune cells recruited into wounded tissue, and remain for about 24?h before undergoing apoptosis.17 They play a central role in both killing microbes and promoting wound healing.18 Neutrophils control invading pathogens by secreting a variety of antimicrobial substancesreactive oxygen species (ROS), antimicrobial peptides, and antimicrobial proteasesand by phagocytosing them with the help Rabbit Polyclonal to PPGB (Cleaved-Arg326) of neutrophil extracellular traps (NETs).19,20 Neutrophils also secrete various cytokines and growth factors, including IL-17 and vascular endothelial growth factor (VEGF). Cytokines and growth factors are both chemotactic for inflammatory cells, and promote the proliferation of fibroblasts, keratinocytes, and endothelial cells.18,21 Demonstrating the importance of neutrophils during wound healing, perturbation of neutrophil recruitment during the early phase of wound healing by knocking out C-X-C motif chemokine receptor 2 (CXCR2) in mice impairs wound healing.22 CXCR2 is an essential mediator of neutrophil chemotaxis via the release of numerous chemokine ligands, including C-X-C chemokine ligand (CXCL)-1, -5, and -8, by keratinocytes at the K02288 kinase activity assay wound site.23 However, CXCR2 knock-out mice also exhibit altered temporal patterns of monocyte infiltration, decreased secretion of IL-1, and reduced keratinocyte migration and proliferation, so impaired wound healing may be the result of numerous compounding factors. 22 Another study found accelerated wound closure and reepithelialization in neutrophil-depleted mice, suggesting a relatively complex role of neutrophils during skin repair.24 Cytokines released by neutrophils during apoptosis are chemotactic for monocytes, which start to arrive 5 to 6?h postinjury. These monocytes differentiate into macrophages, which can remain for several weeks at the wound site.17 Monocyte-derived macrophages have been widely studied in the context of wound healing, and are often considered to be the most important immune cell type in this process.25,26 In addition to macrophages deriving from mobilized monocytes, there is a populace of tissue-resident macrophages in most tissues that can proliferate upon injury.9 While, it has been demonstrated in a murine wound model that tissue-resident macrophages have little impact on the timing of the wound healing process or tissue integrity following resolution,27 their role in skin wound healing is still elusive. Macrophages undergo phenotypic changes throughout the healing process, which helps transition the wound microenvironment from a proinflammatory into a pro-resolution state.9 The most commonly studied phenotypes are the proinflammatorycommonly referred to as classically activated or M1and anti-inflammatoryreferred to as alternatively activated or M2macrophages. Indeed, this M1 and M2 classification originated from characterization, but a altered classification system has been recently proposed to link macrophage populations to activation pathways [(anti-inflammatory, proinflammatory, profibrotic, etc.). Many studies have confirmed that macrophages are critical for proper wound healing.29C32 Upon initial infiltration, proinflammatory macrophages (the so-called M1) remove cellular debris, damaged matrix, microbes, and neutrophils. They also secrete proinflammatory cytokines and growth factors (including IL-1, fibroblast growth factor [FGF]-2, PDGF, and VEGF), which mobilize more immune cells, and promote the proliferation of keratinocytes, fibroblasts, and epithelial cells. During the formation of new tissue, micro environmental cues trigger macrophages to transition into a functionally and K02288 kinase activity assay phenotypically anti-inflammatory state (the so-called M2). At this point,.