Abstract
Macrophages are essential immune cells necessary for regulated inflammation during wound healing. Recent studies have identified that Notch plays a role in macrophage-mediated inflammation. Thus, we investigated the role of Notch signaling on wound macrophage phenotype and function during normal and diabetic wound healing. We found that Notch receptor and ligand expression are dynamic in wound macrophages during normal healing. Mice with a myeloid-specific Notch signaling defect (DNMAMLfloxedLyz2Cre+) demonstrated delayed early healing (days 1–3) and wound macrophages had decreased inflammatory gene expression. In our physiologic murine model of type 2 diabetes (T2D), Notch receptor expression was significantly increased in wound macrophages on day 6, following the initial inflammatory phase of wound healing, corresponding to increased inflammatory cytokine expression. This increase in Notch1 and Notch2 was also observed in human monocytes from patients with T2D. Further, in prediabetic mice with a genetic Notch signaling defect (DNMAMLfloxedLyz2Cre+ on a high-fat diet), improved wound healing was seen at late time points (days 6–7). These findings suggest that Notch is critical for the early inflammatory phase of wound healing and directs production of macrophage-dependent inflammatory mediators. These results identify that canonical Notch signaling is important in directing macrophage function in wound repair and define a translational target for the treatment of non-healing diabetic wounds.
Highlights
According to the CDC, over 1 in 10 Americans suffers from type 2 diabetes (T2D) [1]
Since inflammation is critical in the early stages post-injury to direct the healing cascade and Notch signaling plays a role in inflammation in atherosclerosis and other diseases, we sought to determine if Notch receptors/ligands were dynamic in macrophages during early wound healing [18, 19]
Since we found that Notch1, Notch2, and DLL4 expression was dynamic during wound healing in macrophages over time, we performed flow cytometry to determine if these gene expression findings corresponded to receptor/ligand protein in macrophages
Summary
As the diabetes epidemic exponentially grows, secondary complications of diabetes, such as impaired wound healing, are increasing disproportionately. Non-healing T2D wounds represent a significant economic burden, costing 200 billion dollars annually. Impaired wound healing is among the leading causes of hospital admission in T2D patients and is the leading cause of lower extremity amputation [2]. Amputations in these patients lead to drastic increases in morbidity and mortality as the 5-year mortality rate postamputation is over 50% [2,3,4,5].
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