Impaired wound healing in patients with diabetes mellitus (DM) is a major source of morbidity and mortality. Current treatments for diabetic wounds are modestly effective at promoting healing. Recently, we identified an important role for inflammatory macrophage VEGF-A production in consequent angiogenesis/arteriogenesis required for adequate wound healing. We sought to understand the impact of diabetes on inflammatory angiogenesis and consequent healing. We hypothesized that diabetes mellitus (DM) results in reduced inflammatory macrophage VEGF-A expression with consequent impairments in angiogenesis-dependent wound healing. Mice with experimental diabetes demonstrated profound delays both in wound healing using a dermal punch biopsy model and in perfusion recovery using the femoral artery ligation model of hind limb ischemia. VEGF-A expression is highly upregulated in “classic inflammatory” macrophages relative to “alternatively activated” or wound healing macrophages. This is supported by a strong association between IL-1β and VEGF-A expression. In order to understand whether this relationship between IL-1β and VEGF-A was causal, we generated a novel mouse with a LoxP flanked IL-1β allele to create an inducible macrophage deletion of IL-1β. Myeloid IL-β deletion resulted in severely impaired macrophage VEGF-A expression and consequent decreases in angiogenesis and wound healing, consistent with the experimental model of DM. Moreover, macrophages from diabetic mice demonstrated reduced expression of IL-1R signaling complex components along with consequent reductions in VEGF-A expression. Defining inflammatory macrophages as key, early drivers of angiogenesis supports a paradigm shift away from inflammation-suppression for adequate wound healing, allowing for macrophage reprograming strategies that promote appropriate inflammation-dependent healing responses.
C.S. Mantsounga: None.
National Institutes Health (1R01HL139795)